2-178647040-GTATATATATA-GTATATATATATATA

Position:

• chr2-178647040-GTATATATATA-GTATATATATATATA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001267550.2(TTN):​c.40222+23_40222+24insTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 730,512 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 21)
  • Exomes 𝑓: 0.0039 (1 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• 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 -10 ACMG points.

• BP6: Variant 2-178647040-G-GTATA is Benign according to our data. Variant chr2-178647040-G-GTATA is described in ClinVar as [Likely_benign]. Clinvar id is 1193112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0173 (2480/143300) while in subpopulation EAS AF= 0.0423 (206/4868). AF 95% confidence interval is 0.0376. There are 29 homozygotes in gnomad4. There are 1251 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.40222+23_40222+24insTATA		intron_variant		ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+2558_2185+2561dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.40222+23_40222+24insTATA		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+49378_502+49381dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2484 AN: 143234 Hom.: 30 Cov.: 21

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0160

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0102

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.0121 AC: 186 AN: 15314 Hom.: 0 AF XY: 0.0117 AC XY: 92 AN XY: 7862

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.0167

Gnomad SAS exome AF: 0.00155

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.00386 AC: 2269 AN: 587212 Hom.: 1 Cov.: 0 AF XY: 0.00398 AC XY: 1162 AN XY: 291970

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.00345

Gnomad4 ASJ exome AF: 0.00758

Gnomad4 EAS exome AF: 0.0187

Gnomad4 SAS exome AF: 0.00200

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.0173 AC: 2480 AN: 143300 Hom.: 29 Cov.: 21 AF XY: 0.0180 AC XY: 1251 AN XY: 69516

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.0160

Gnomad4 EAS AF: 0.0423

Gnomad4 SAS AF: 0.00563

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.00504

Gnomad4 OTH AF: 0.0148

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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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;