2-178654252-A-G

Position:

chr2-178654252-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.38336T>C(p.Val12779Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,598,794 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 7 hom., cov: 22)

Exomes 𝑓: 0.00079 ( 71 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.147

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073044896).

BP6

Variant 2-178654252-A-G is Benign according to our data. Variant chr2-178654252-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 220852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178654252-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00283 (422/149032) while in subpopulation EAS AF= 0.00606 (31/5114). AF 95% confidence interval is 0.00539. There are 7 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.38336T>C	p.Val12779Ala	missense_variant	193/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+9751A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.38336T>C	p.Val12779Ala	missense_variant	193/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+56571A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

421

AN:

148924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00597

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00325

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00624

Gnomad SAS

AF:

0.00389

Gnomad FIN

AF:

0.00106

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000991

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00145

AC:

347

AN:

238830

Hom.:

AF XY:

0.00142

AC XY:

186

AN XY:

130632

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.00155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00321

Gnomad SAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.000616

Gnomad NFE exome

AF:

0.000641

Gnomad OTH exome

AF:

0.00186

GnomAD4 exome

AF:

0.000790

AC:

1146

AN:

1449762

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

610

AN XY:

721074

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00762

Gnomad4 SAS exome

AF:

0.00279

Gnomad4 FIN exome

AF:

0.000993

Gnomad4 NFE exome

AF:

0.000269

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00283

AC:

422

AN:

149032

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

228

AN XY:

72506

show subpopulations

Gnomad4 AFR

AF:

0.00601

Gnomad4 AMR

AF:

0.00324

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00606

Gnomad4 SAS

AF:

0.00389

Gnomad4 FIN

AF:

0.00106

Gnomad4 NFE

AF:

0.000991

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00111

Hom.:

ExAC

AF:

0.00203

AC:

242

EpiCase

AF:

0.00115

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TTN: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 13, 2018	- -

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

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.76

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0073

MutationTaster

Benign

1.0

N;N;N;N;N;N

Vest4

0.16

MVP

0.84

GERP RS

0.92

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