rs2627038

Positions:

• chr2-178689190-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.32012-54C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 1,587,678 control chromosomes in the GnomAD database, including 15,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (5387 hom., cov: 30)
  • Exomes 𝑓: 0.087 (10375 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51

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]

LOC124907912 (HGNC:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-178689190-G-A is Benign according to our data. Variant chr2-178689190-G-A is described in ClinVar as [Benign]. Clinvar id is 671274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.32012-54C>T		intron_variant		ENST00000589042.5	NP_001254479.2
LOC124907912	XR_007087321.1	n.1053G>A		non_coding_transcript_exon_variant	1/2
LOC124906100	XR_007087318.1	n.2186-24564G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.32012-54C>T		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-45314G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30191 AN: 151496 Hom.: 5345 Cov.: 30

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.0873 AC: 125438 AN: 1436064 Hom.: 10375 Cov.: 31 AF XY: 0.0896 AC XY: 63914 AN XY: 713336

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.0700

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.0559

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.200 AC: 30305 AN: 151614 Hom.: 5387 Cov.: 30 AF XY: 0.204 AC XY: 15147 AN XY: 74112

Gnomad4 AFR AF: 0.465

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.0583

Gnomad4 OTH AF: 0.164

Alfa AF: 0.137 Hom.: 530

Bravo AF: 0.216

Asia WGS AF: 0.213 AC: 738 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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	-0.91
CADD	Benign	0.0090
DANN	Benign	0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2627038; hg19: chr2-179553917; COSMIC: COSV60438961;