2-178647040-GTATATATATA-GTATATATA

Position:

• chr2-178647040-GTATATATATA-GTATATATA

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+22_40222+23del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 697,118 control chromosomes in the GnomAD database, including 3,591 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3309 hom., cov: 21)
  • Exomes 𝑓: 0.25 (282 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.194

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-GTA-G is Benign according to our data. Variant chr2-178647040-GTA-G is described in ClinVar as [Likely_benign]. Clinvar id is 192211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178647040-GTA-G is described in Lovd as [Benign]. Variant chr2-178647040-GTA-G is described in Lovd as [Likely_benign]. Variant chr2-178647040-GTA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.40222+22_40222+23del		intron_variant		ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+2560_2185+2561del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.40222+22_40222+23del		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+49380_502+49381del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.158 AC: 22513 AN: 142842 Hom.: 3286 Cov.: 21

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.0500

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.0884

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.388 AC: 5946 AN: 15314 Hom.: 8 AF XY: 0.389 AC XY: 3062 AN XY: 7862

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.367

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.252 AC: 139575 AN: 554210 Hom.: 282 AF XY: 0.256 AC XY: 70479 AN XY: 275132

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.158 AC: 22589 AN: 142908 Hom.: 3309 Cov.: 21 AF XY: 0.164 AC XY: 11330 AN XY: 69288

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.0331

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0935

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;