2-178595584-C-T

Position:

chr2-178595584-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001267550.2(TTN):c.57770G>A(p.Arg19257Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,580,790 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 7.86

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01005879).

BP6

Variant 2-178595584-C-T is Benign according to our data. Variant chr2-178595584-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 180572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.57770G>A	p.Arg19257Gln	missense_variant	295/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.57770G>A	p.Arg19257Gln	missense_variant	295/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000297

AC:

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00210

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000431

AC:

AN:

199500

Hom.:

AF XY:

0.000440

AC XY:

AN XY:

106712

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000394

Gnomad FIN exome

AF:

0.00307

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000966

GnomAD4 exome

AF:

0.000225

AC:

322

AN:

1429050

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

158

AN XY:

707610

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.000175

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.0000522

Gnomad4 SAS exome

AF:

0.000122

Gnomad4 FIN exome

AF:

0.00398

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000422

GnomAD4 genome

AF:

0.000297

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

AN XY:

74036

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00210

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000400

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Dec 17, 2013

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 17, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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

Pathogenic

0.70

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

MetaRNN

Benign

0.010

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.8

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

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.3

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.46

MVP

0.43

MPC

0.50

ClinPred

0.080

GERP RS

6.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over