2-178698916-TAA-T

Position:

• chr2-178698916-TAA-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.30683-4_30683-3del 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 0.0119 in 1,239,238 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 30)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.954

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 -12 ACMG points.

• BP6: Variant 2-178698916-TAA-T is Benign according to our data. Variant chr2-178698916-TAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 695340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178698916-TAA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0128 (14750/1154170) while in subpopulation AMR AF= 0.0322 (622/19314). AF 95% confidence interval is 0.0301. There are 0 homozygotes in gnomad4_exome. There are 7520 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30683-4_30683-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2186-14824_2186-14823del		intron_variant, non_coding_transcript_variant
LOC124907912	XR_007087321.1	n.7314+3479_7314+3480del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.30683-4_30683-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.503-35574_503-35573del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000317 AC: 27 AN: 85050 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000363

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0344 AC: 2265 AN: 65808 Hom.: 0 AF XY: 0.0339 AC XY: 1213 AN XY: 35820

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0420

Gnomad SAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0128 AC: 14750 AN: 1154170 Hom.: 0 AF XY: 0.0132 AC XY: 7520 AN XY: 569540

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.0271

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.000317 AC: 27 AN: 85068 Hom.: 0 Cov.: 30 AF XY: 0.000443 AC XY: 18 AN XY: 40598

Gnomad4 AFR AF: 0.000185

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.000363

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 20, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2017

- -

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: rs368277751; hg19: chr2-179563643;