chr2-178576312-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_001267550.2(TTN):c.69820G>A(p.Gly23274Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G23274D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.86

Publications

0 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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-178576312-C-T is Benign according to our data. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178576312-C-T is described in CliVar as Likely_benign. Clinvar id is 192160.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.69820G>A	p.Gly23274Ser	missense_variant	Exon 326 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.69820G>A	p.Gly23274Ser	missense_variant	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000474

AC:

AN:

210786

AF XY:

0.00000878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1423214

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31624

American (AMR)

AF:

0.00

AC:

AN:

37460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23684

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096562

Other (OTH)

AF:

0.00

AC:

AN:

58688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.71

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D

MetaSVM

Benign

-0.38

MutationAssessor

Benign

2.0

.;.;.;M;.;.;M

PhyloP100

7.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

D;D;.;.;D;D;.

REVEL

Uncertain

0.51

Sift

Benign

0.035

D;D;.;.;D;D;.

Polyphen

1.0

.;.;.;D;.;.;D

Vest4

0.50

MutPred

0.72

.;.;.;Gain of catalytic residue at G21633 (P = 0.0249);.;.;Gain of catalytic residue at G21633 (P = 0.0249);

MVP

0.37

MPC

0.46

ClinPred

0.20

GERP RS

5.9

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over