chr2-178752043-GAAA-G

Position:

• chr2-178752043-GAAA-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_133379.5(TTN):​c.10361-7_10361-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,396,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: TTN NM_133379.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: 3.55

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 2-178752043-GAAA-G is Benign according to our data. Variant chr2-178752043-GAAA-G is described in ClinVar as [Benign]. Clinvar id is 1174725.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-178752043-GAAA-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+1078_11311+1080del		intron_variant		ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10361-7_10361-5del		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.10361-7_10361-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+1078_11311+1080del		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1224-4210_1224-4208del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 22 AN: 140934 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000783

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.000240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000186

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000878 AC: 1102 AN: 1255490 Hom.: 0 AF XY: 0.000894 AC XY: 562 AN XY: 628570

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.000838

Gnomad4 ASJ exome AF: 0.00100

Gnomad4 EAS exome AF: 0.000317

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.00108

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.000574

GnomAD4 genome AF: 0.000156 AC: 22 AN: 140988 Hom.: 0 Cov.: 0 AF XY: 0.000132 AC XY: 9 AN XY: 68254

Gnomad4 AFR AF: 0.0000781

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.000240

Gnomad4 NFE AF: 0.000186

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;