chrX-111251613-C-A

Variant names:

• chrX-111251613-C-A
• NM_014289.4:c.829G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014289.4(CAPN6):​c.829G>T​(p.Val277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025327563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN6	NM_014289.4	c.829G>T	p.Val277Leu	missense_variant	Exon 6 of 13	ENST00000324068.2	NP_055104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN6	ENST00000324068.2	c.829G>T	p.Val277Leu	missense_variant	Exon 6 of 13	1	NM_014289.4	ENSP00000317214.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096627 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362013

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.38
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.78	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.010
MutPred		0.24		Loss of MoRF binding (P = 0.1034);
MVP		0.12
MPC		0.44
ClinPred		0.24	T
GERP RS		5.3
Varity_R		0.068
gMVP		0.40

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-110494841;