2-178526912-CT-C

Position:

• chr2-178526912-CT-C

Variant summary

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

The NM_001267550.2(TTN):​c.*99del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (18 hom., cov: 0)
  • Exomes 𝑓: 0.023 (331 hom.)
• Consequence: TTN NM_001267550.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.858

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 2-178526912-CT-C is Benign according to our data. Variant chr2-178526912-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1204371.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178526912-CT-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0161 (2453/152002) while in subpopulation NFE AF= 0.0229 (1557/67958). AF 95% confidence interval is 0.022. There are 18 homozygotes in gnomad4. There are 1230 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.*99del		3_prime_UTR_variant	363/363	ENST00000589042.5	NP_001254479.2
TTN-AS1	NR_038272.1	n.219+3284del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.*99del		3_prime_UTR_variant	363/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.416+3284del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2455 AN: 151884 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.00508

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0231 AC: 23720 AN: 1025538 Hom.: 331 Cov.: 13 AF XY: 0.0225 AC XY: 11315 AN XY: 501946

Gnomad4 AFR exome AF: 0.00408

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00414

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00614

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0161 AC: 2453 AN: 152002 Hom.: 18 Cov.: 0 AF XY: 0.0166 AC XY: 1230 AN XY: 74294

Gnomad4 AFR AF: 0.00504

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.0307

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.00309 Hom.: 129

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

Jun 26, 2018

- -

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: rs11424072; hg19: chr2-179391639;