2-178647040-GTATATATATA-GTATATATATATA

Position:

• chr2-178647040-GTATATATATA-GTATATATATATA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.40222+23_40222+24insTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 720,988 control chromosomes in the GnomAD database, including 285 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (262 hom., cov: 21)
  • Exomes 𝑓: 0.053 (23 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.212

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-178647040-G-GTA is Benign according to our data. Variant chr2-178647040-G-GTA is described in ClinVar as [Likely_benign]. Clinvar id is 192212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40222+23_40222+24insTA		intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+2560_2185+2561dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40222+23_40222+24insTA		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+49380_502+49381dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8438 AN: 143074 Hom.: 262 Cov.: 21

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.0422

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0453

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0850

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.0731

GnomAD3 exomes AF: 0.0796 AC: 1219 AN: 15314 Hom.: 0 AF XY: 0.0790 AC XY: 621 AN XY: 7862

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0167

Gnomad SAS exome AF: 0.0543

Gnomad FIN exome AF: 0.0921

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0526 AC: 30375 AN: 577846 Hom.: 23 Cov.: 0 AF XY: 0.0538 AC XY: 15452 AN XY: 287300

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.0450

Gnomad4 ASJ exome AF: 0.0814

Gnomad4 EAS exome AF: 0.0479

Gnomad4 SAS exome AF: 0.0551

Gnomad4 FIN exome AF: 0.0658

Gnomad4 NFE exome AF: 0.0522

Gnomad4 OTH exome AF: 0.0502

GnomAD4 genome AF: 0.0589 AC: 8437 AN: 143142 Hom.: 262 Cov.: 21 AF XY: 0.0602 AC XY: 4182 AN XY: 69426

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.0642

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.0452

Gnomad4 SAS AF: 0.0693

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.0684

Gnomad4 OTH AF: 0.0726

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;