11-65182882-T-TC

Variant names:

• chr11-65182882-T-TC
• NM_005186.4:c.181_182insC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005186.4(CAPN1):​c.181_182insC​(p.Phe61SerfsTer106) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN1 NM_005186.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.42

Genes affected

CAPN1 (HGNC:1476): (calpain 1) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-65182882-T-TC is Pathogenic according to our data. Variant chr11-65182882-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 1802257.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.181_182insC	p.Phe61SerfsTer106	frameshift_variant	Exon 2 of 22	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.181_182insC	p.Phe61SerfsTer106	frameshift_variant	Exon 2 of 22	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive spastic paraplegia type 76 Pathogenic:1

Sep 28, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181_182insC is not present in publicly available population databases like 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. The heterozygous state of the variant is present in ExAC and gnomAD, at a low frequency. The variant has neither been published in literature nor reported to clinical databases like ClinVar, Human Genome Mutation Database (HGMD) and/or OMIM, in any affected individuals. In silico pathogenicity programs like Mutation Taster, CADD, Varsome etc. predicted this variant to be likely deleterious. The variant causes frameshift at the 61st amino acid position of the original transcript, creating a premature stop signal at the 166th amino acid position of the altered transcript, which may either result in translation of a truncated protein or cause nonsense mediated decay of the mRNA. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64950353;