chr2-178770209-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):​c.8492G>A​(p.Ser2831Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,076 control chromosomes in the GnomAD database, including 4,018 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 389 hom., cov: 32)
Exomes 𝑓: 0.055 ( 3629 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

1
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 3.00

Publications

25 publications found
Variant links:
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0010921359).
BP6
Variant 2-178770209-C-T is Benign according to our data. Variant chr2-178770209-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.8492G>A p.Ser2831Asn missense_variant Exon 36 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkc.8492G>A p.Ser2831Asn missense_variant Exon 36 of 46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.8492G>A p.Ser2831Asn missense_variant Exon 36 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkc.8492G>A p.Ser2831Asn missense_variant Exon 36 of 46 5 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.0517
AC:
7860
AN:
152110
Hom.:
387
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0119
Gnomad AMI
AF:
0.0482
Gnomad AMR
AF:
0.140
Gnomad ASJ
AF:
0.0560
Gnomad EAS
AF:
0.185
Gnomad SAS
AF:
0.0464
Gnomad FIN
AF:
0.0512
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0466
Gnomad OTH
AF:
0.0483
GnomAD2 exomes
AF:
0.0829
AC:
20816
AN:
251236
AF XY:
0.0746
show subpopulations
Gnomad AFR exome
AF:
0.0110
Gnomad AMR exome
AF:
0.240
Gnomad ASJ exome
AF:
0.0568
Gnomad EAS exome
AF:
0.203
Gnomad FIN exome
AF:
0.0525
Gnomad NFE exome
AF:
0.0458
Gnomad OTH exome
AF:
0.0699
GnomAD4 exome
AF:
0.0550
AC:
80440
AN:
1461848
Hom.:
3629
Cov.:
33
AF XY:
0.0539
AC XY:
39165
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00989
AC:
331
AN:
33480
American (AMR)
AF:
0.228
AC:
10215
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0552
AC:
1442
AN:
26136
East Asian (EAS)
AF:
0.194
AC:
7681
AN:
39686
South Asian (SAS)
AF:
0.0415
AC:
3578
AN:
86258
European-Finnish (FIN)
AF:
0.0546
AC:
2918
AN:
53420
Middle Eastern (MID)
AF:
0.0198
AC:
114
AN:
5768
European-Non Finnish (NFE)
AF:
0.0457
AC:
50869
AN:
1111982
Other (OTH)
AF:
0.0545
AC:
3292
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
5318
10636
15954
21272
26590
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2118
4236
6354
8472
10590
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0517
AC:
7866
AN:
152228
Hom.:
389
Cov.:
32
AF XY:
0.0537
AC XY:
3993
AN XY:
74412
show subpopulations
African (AFR)
AF:
0.0118
AC:
492
AN:
41562
American (AMR)
AF:
0.140
AC:
2141
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.0560
AC:
194
AN:
3466
East Asian (EAS)
AF:
0.185
AC:
955
AN:
5158
South Asian (SAS)
AF:
0.0465
AC:
224
AN:
4820
European-Finnish (FIN)
AF:
0.0512
AC:
543
AN:
10598
Middle Eastern (MID)
AF:
0.0170
AC:
5
AN:
294
European-Non Finnish (NFE)
AF:
0.0466
AC:
3169
AN:
68008
Other (OTH)
AF:
0.0468
AC:
99
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
367
734
1100
1467
1834
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
88
176
264
352
440
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0527
Hom.:
1408
Bravo
AF:
0.0618
TwinsUK
AF:
0.0477
AC:
177
ALSPAC
AF:
0.0506
AC:
195
ESP6500AA
AF:
0.0134
AC:
59
ESP6500EA
AF:
0.0451
AC:
388
ExAC
AF:
0.0759
AC:
9220
Asia WGS
AF:
0.0870
AC:
300
AN:
3476
EpiCase
AF:
0.0427
EpiControl
AF:
0.0453

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Aug 15, 2013
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Mar 19, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Ser2831Asn in exon 36 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 4.8% (332/7020) of European American chromosomes and 1.4% (52/3738) of African American chromosomes from a broad popu lation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2306636) -

Oct 19, 2012
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 06, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Early-onset myopathy with fatal cardiomyopathy Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dilated cardiomyopathy 1G Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Cardiovascular phenotype Benign:1
Aug 23, 2012
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.044
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
21
DANN
Benign
0.94
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.34
N
LIST_S2
Benign
0.33
T;T;T;.;T;T;T;T
MetaRNN
Benign
0.0011
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PhyloP100
3.0
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
2.5
N;N;.;.;N;N;.;N
REVEL
Benign
0.14
Sift
Benign
1.0
T;T;.;.;T;T;.;T
Sift4G
Benign
1.0
.;.;.;.;.;.;.;T
Polyphen
0.0
.;.;.;B;.;.;B;B
Vest4
0.016
MPC
0.078
ClinPred
0.011
T
GERP RS
6.1
Mutation Taster
=95/5
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs2306636; hg19: chr2-179634936; COSMIC: COSV59946607; COSMIC: COSV59946607; API