rs76771282

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001267550.2(TTN):​c.19383T>C​(p.Asn6461Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,612,620 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 0 hom., cov: 33)
Exomes 𝑓: 0.010 ( 95 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25

Conservation

PhyloP100: 1.34

Publications

2 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 2-178728543-A-G is Benign according to our data. Variant chr2-178728543-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.34 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00605 (921/152198) while in subpopulation NFE AF = 0.0107 (725/67976). AF 95% confidence interval is 0.01. There are 0 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 95 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TTN
NM_001267550.2
MANE Select
c.19383T>Cp.Asn6461Asn
synonymous
Exon 66 of 363NP_001254479.2
TTN
NM_001256850.1
c.18432T>Cp.Asn6144Asn
synonymous
Exon 64 of 313NP_001243779.1
TTN
NM_133378.4
c.15651T>Cp.Asn5217Asn
synonymous
Exon 63 of 312NP_596869.4

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TTN
ENST00000589042.5
TSL:5 MANE Select
c.19383T>Cp.Asn6461Asn
synonymous
Exon 66 of 363ENSP00000467141.1
TTN
ENST00000446966.2
TSL:1
c.19383T>Cp.Asn6461Asn
synonymous
Exon 66 of 361ENSP00000408004.2
TTN
ENST00000436599.2
TSL:1
c.19107T>Cp.Asn6369Asn
synonymous
Exon 64 of 361ENSP00000405517.2

Frequencies

GnomAD3 genomes
AF:
0.00606
AC:
922
AN:
152080
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00232
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.00256
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0107
Gnomad OTH
AF:
0.00479
GnomAD2 exomes
AF:
0.00623
AC:
1542
AN:
247676
AF XY:
0.00638
show subpopulations
Gnomad AFR exome
AF:
0.00156
Gnomad AMR exome
AF:
0.000963
Gnomad ASJ exome
AF:
0.00130
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00480
Gnomad NFE exome
AF:
0.0113
Gnomad OTH exome
AF:
0.00417
GnomAD4 exome
AF:
0.0100
AC:
14634
AN:
1460422
Hom.:
95
Cov.:
32
AF XY:
0.00976
AC XY:
7090
AN XY:
726354
show subpopulations
African (AFR)
AF:
0.00126
AC:
42
AN:
33440
American (AMR)
AF:
0.00152
AC:
68
AN:
44596
Ashkenazi Jewish (ASJ)
AF:
0.000997
AC:
26
AN:
26086
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39572
South Asian (SAS)
AF:
0.00236
AC:
203
AN:
86156
European-Finnish (FIN)
AF:
0.00583
AC:
311
AN:
53342
Middle Eastern (MID)
AF:
0.000869
AC:
5
AN:
5752
European-Non Finnish (NFE)
AF:
0.0122
AC:
13559
AN:
1111166
Other (OTH)
AF:
0.00696
AC:
420
AN:
60312
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
880
1760
2640
3520
4400
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
516
1032
1548
2064
2580
<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:
0.00605
AC:
921
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.00536
AC XY:
399
AN XY:
74386
show subpopulations
African (AFR)
AF:
0.00231
AC:
96
AN:
41562
American (AMR)
AF:
0.00255
AC:
39
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5176
South Asian (SAS)
AF:
0.00104
AC:
5
AN:
4814
European-Finnish (FIN)
AF:
0.00377
AC:
40
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0107
AC:
725
AN:
67976
Other (OTH)
AF:
0.00474
AC:
10
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
52
104
155
207
259
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
20
40
60
80
100
<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:
0.00689
Hom.:
6
Bravo
AF:
0.00601
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00923
EpiControl
AF:
0.00886

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
8
not specified (8)
-
-
5
not provided (5)
-
-
2
Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-
-
2
Early-onset myopathy with fatal cardiomyopathy (2)
-
-
2
Myopathy, myofibrillar, 9, with early respiratory failure (2)
-
-
2
Tibial muscular dystrophy (2)
-
-
1
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-
-
1
Cardiomyopathy (1)
-
-
1
Cardiovascular phenotype (1)
-
-
1
Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.53
CADD
Benign
2.1
DANN
Benign
0.61
PhyloP100
1.3
Mutation Taster
=81/19
polymorphism

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: rs76771282; hg19: chr2-179593270; API