chr2-178752043-G-GA

Position:

• chr2-178752043-G-GA

Variant summary

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

The NM_133379.5(TTN):​c.10361-5_10361-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (33 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1 hom.)
• Consequence: TTN NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.56

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

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 2-178752043-G-GA is Benign according to our data. Variant chr2-178752043-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 1207954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (1968/140942) while in subpopulation AFR AF= 0.0409 (1572/38390). AF 95% confidence interval is 0.0393. There are 33 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+1080_11311+1081insT		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10361-5_10361-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.10361-5_10361-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+1080_11311+1081insT		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1224-4208dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 1961 AN: 140890 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00442

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0214 AC: 26556 AN: 1241994 Hom.: 1 Cov.: 0 AF XY: 0.0215 AC XY: 13351 AN XY: 621590

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.0625

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.0271

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0140 AC: 1968 AN: 140942 Hom.: 33 Cov.: 0 AF XY: 0.0136 AC XY: 928 AN XY: 68228

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00442

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.000205

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.0171

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs58651353; hg19: chr2-179616770;