chr2-178554496-G-C

Variant names:

• chr2-178554496-G-C
• rs201241167
• NM_001267550.2:c.88851C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001267550.2(TTN):​c.88851C>G​(p.Gly29617Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G29617G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.383
• Publications: 2 publications found

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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-178554496-G-C is Benign according to our data. Variant chr2-178554496-G-C is described in ClinVar as Benign. ClinVar VariationId is 137811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.383 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.88851C>G	p.Gly29617Gly	synonymous_variant	Exon 332 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.88851C>G	p.Gly29617Gly	synonymous_variant	Exon 332 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151656 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0792 AC: 14932 AN: 188456 AF XY: 0.0821

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.0899

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0798

Gnomad OTH exome AF: 0.0545

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00896 AC: 12768 AN: 1424704 Hom.: 0 Cov.: 32 AF XY: 0.0103 AC XY: 7241 AN XY: 705154

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0161 AC: 526 AN: 32682

American (AMR) AF: 0.0565 AC: 2256 AN: 39960

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 633 AN: 25050

East Asian (EAS) AF: 0.0318 AC: 1214 AN: 38198

South Asian (SAS) AF: 0.0167 AC: 1342 AN: 80208

European-Finnish (FIN) AF: 0.0357 AC: 1660 AN: 46538

Middle Eastern (MID) AF: 0.00488 AC: 27 AN: 5536

European-Non Finnish (NFE) AF: 0.00428 AC: 4696 AN: 1097344

Other (OTH) AF: 0.00699 AC: 414 AN: 59188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000593 AC: 9 AN: 151764 Hom.: 0 Cov.: 33 AF XY: 0.0000675 AC XY: 5 AN XY: 74114

⚠️ 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: 41500

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67686

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000222045), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0244 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 26, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.023
DANN	Benign	0.68
PhyloP100		-0.38
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201241167; hg19: chr2-179419223; COSMIC: COSV59887949; COSMIC: COSV59887949;