rs2742327

Variant names:

• chr2-178722960-T-C
• rs2742327
• NM_001267550.2:c.21962-23A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.21962-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,598,260 control chromosomes in the GnomAD database, including 62,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (11036 hom., cov: 33)
  • Exomes 𝑓: 0.24 (51920 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.850
• Publications: 16 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-178722960-T-C is Benign according to our data. Variant chr2-178722960-T-C is described in ClinVar as Benign. ClinVar VariationId is 671270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.21962-23A>G		intron_variant	Intron 75 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.21962-23A>G		intron_variant	Intron 75 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52093 AN: 151876 Hom.: 10988 Cov.: 33

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.316

GnomAD2 exomes AF: 0.318 AC: 74865 AN: 235794 AF XY: 0.310

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.245 AC: 354080 AN: 1446266 Hom.: 51920 Cov.: 35 AF XY: 0.247 AC XY: 177677 AN XY: 718002

African (AFR) AF: 0.567 AC: 18419 AN: 32494

American (AMR) AF: 0.416 AC: 17472 AN: 42002

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5091 AN: 25416

East Asian (EAS) AF: 0.649 AC: 25618 AN: 39486

South Asian (SAS) AF: 0.418 AC: 34846 AN: 83300

European-Finnish (FIN) AF: 0.204 AC: 10767 AN: 52826

Middle Eastern (MID) AF: 0.280 AC: 1587 AN: 5660

European-Non Finnish (NFE) AF: 0.203 AC: 224103 AN: 1105506

Other (OTH) AF: 0.272 AC: 16177 AN: 59576

GnomAD4 genome AF: 0.343 AC: 52202 AN: 151994 Hom.: 11036 Cov.: 33 AF XY: 0.349 AC XY: 25936 AN XY: 74300

African (AFR) AF: 0.553 AC: 22917 AN: 41462

American (AMR) AF: 0.375 AC: 5721 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 706 AN: 3468

East Asian (EAS) AF: 0.651 AC: 3359 AN: 5156

South Asian (SAS) AF: 0.432 AC: 2077 AN: 4810

European-Finnish (FIN) AF: 0.204 AC: 2160 AN: 10584

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14032 AN: 67938

Other (OTH) AF: 0.318 AC: 670 AN: 2108

Alfa AF: 0.265 Hom.: 2462

Bravo AF: 0.368

Asia WGS AF: 0.544 AC: 1891 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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	-0.89
CADD	Benign	4.5
DANN	Benign	0.55
PhyloP100		-0.85
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2742327; hg19: chr2-179587687; COSMIC: COSV59864550; COSMIC: COSV59864550;