chr2-178632329-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.43565A>G​(p.His14522Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,605,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H14522D) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000021 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
6
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 7.97

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14579228).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.43565A>G p.His14522Arg missense_variant Exon 236 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.43565A>G p.His14522Arg missense_variant Exon 236 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152032
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000550
AC:
13
AN:
236512
AF XY:
0.0000156
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000905
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000474
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000172
GnomAD4 exome
AF:
0.0000213
AC:
31
AN:
1453734
Hom.:
0
Cov.:
32
AF XY:
0.0000152
AC XY:
11
AN XY:
722504
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33360
American (AMR)
AF:
0.0000684
AC:
3
AN:
43850
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25904
East Asian (EAS)
AF:
0.000280
AC:
11
AN:
39264
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84990
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53072
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
9.03e-7
AC:
1
AN:
1107466
Other (OTH)
AF:
0.000266
AC:
16
AN:
60080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000658
AC:
1
AN:
152032
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74220
show subpopulations
āš ļø The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41422
American (AMR)
AF:
0.00
AC:
0
AN:
15252
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000194
AC:
1
AN:
5154
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67986
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
āš ļø The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000663
AC:
8
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Jul 21, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27535533) -

Oct 02, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 28, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Jan 01, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiomyopathy Uncertain:1
Jun 16, 2016
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
May 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1
-
Genetics and Genomics Program, Sidra Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Cardiovascular phenotype Uncertain:1
Sep 12, 2018
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.H5457R variant (also known as c.16370A>G), located in coding exon 63 of the TTN gene, results from an A to G substitution at nucleotide position 16370. The histidine at codon 5457 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
20
DANN
Benign
0.91
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;D;.;D;D;D
M_CAP
Benign
0.0091
T
MetaRNN
Benign
0.15
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.070
D
MutationAssessor
Uncertain
2.6
.;.;.;M;.;.;M
PhyloP100
8.0
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.7
D;D;.;.;D;D;.
REVEL
Uncertain
0.36
Sift
Benign
0.14
T;T;.;.;T;T;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.39
MVP
0.53
MPC
0.51
ClinPred
0.28
T
GERP RS
6.0
Mutation Taster
=47/53
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs374085402; hg19: chr2-179497056; API