X-111250985-CAT-C

Variant names:

• chrX-111250985-CAT-C
• NM_014289.4:c.1088_1089delAT

Variant summary

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

The NM_014289.4(CAPN6):​c.1088_1089delAT​(p.Asp363GlyfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000182 in 1,097,909 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CAPN6 NM_014289.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.90

Genes affected

CAPN6 (HGNC:1483): (calpain 6) Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is highly expressed in the placenta. Its C-terminal region lacks any homology to the calmodulin-like domain of other calpains. The protein lacks critical active site residues and thus is suggested to be proteolytically inactive. The protein may play a role in tumor formation by inhibiting apoptosis and promoting angiogenesis. [provided by RefSeq, Nov 2009]

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 X-111250985-CAT-C is Pathogenic according to our data. Variant chrX-111250985-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 3766451.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN6	NM_014289.4	c.1088_1089delAT	p.Asp363GlyfsTer2	frameshift_variant	Exon 8 of 13	ENST00000324068.2	NP_055104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN6	ENST00000324068.2	c.1088_1089delAT	p.Asp363GlyfsTer2	frameshift_variant	Exon 8 of 13	1	NM_014289.4	ENSP00000317214.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097909 Hom.: 0 AF XY: 0.00000275 AC XY: 1 AN XY: 363271

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental delay Pathogenic:1

Feb 03, 2025

Oasi Research Institute-IRCCS

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

We analyzed a family in which two male siblings presented with severe neurodevelopmental and motor coordination disorders, while the mother and daughter exhibited mild learning disabilities. Whole exome sequencing (WES) identified a pathogenic variant in the CAPN6 gene, found in hemizygous condition in the affected brothers and in heterozygous condition in the mother and daughter. The variant was classified as likely pathogenic according to ACMG criteria (PS4, PM2, PP1) and resulted in truncation of the CAPN6 protein within Domain III, a region critical for interaction with VEGF. In-silico protein structure prediction (Alphafold algorithm) revealed significant alterations in the mutated CAPN6 protein and its interaction with VEGF, caused by the identified mutation. Furthermore, according to GnomAD database, the variant displays a very low allele frequency (0.000001651). -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-110494213;