NM_014289.4:c.894-17_894-15delTTT

Variant names:

• chrX-111251300-GAAA-G
• rs201147886
• NM_014289.4:c.894-17_894-15delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014289.4(CAPN6):​c.894-17_894-15delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 840,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.000029 (0 hom. 0 hem.)
• Consequence: CAPN6 NM_014289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014289.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN6	NM_014289.4	MANE Select	c.894-17_894-15delTTT		intron	N/A	NP_055104.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN6	ENST00000324068.2	TSL:1 MANE Select	c.894-17_894-15delTTT		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.492-17_492-15delTTT		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome AF: 0.0000286 AC: 24 AN: 840332 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 253544

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20061

American (AMR) AF: 0.00 AC: 0 AN: 22406

Ashkenazi Jewish (ASJ) AF: 0.0000650 AC: 1 AN: 15384

East Asian (EAS) AF: 0.0000388 AC: 1 AN: 25767

South Asian (SAS) AF: 0.00 AC: 0 AN: 39035

European-Finnish (FIN) AF: 0.0000299 AC: 1 AN: 33495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2899

European-Non Finnish (NFE) AF: 0.0000326 AC: 21 AN: 644928

Other (OTH) AF: 0.00 AC: 0 AN: 36357

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201147886; hg19: chrX-110494528; COSMIC: COSV60694781;