chrX-111247953-G-T

Variant names:

• chrX-111247953-G-T
• rs776023291
• NM_014289.4:c.1524C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014289.4(CAPN6):​c.1524C>A​(p.Asn508Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.815
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10298613).

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.1524C>A	p.Asn508Lys	missense	Exon 11 of 13	NP_055104.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN6	ENST00000324068.2	TSL:1 MANE Select	c.1524C>A	p.Asn508Lys	missense	Exon 11 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.1122C>A	p.Asn374Lys	missense	Exon 9 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111895 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183225 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096770 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362142

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.0000284 AC: 1 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840812

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111951 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34123

African (AFR) AF: 0.00 AC: 0 AN: 30838

American (AMR) AF: 0.00 AC: 0 AN: 10550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53209

Other (OTH) AF: 0.00 AC: 0 AN: 1541

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.81
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.51	T
Polyphen		0.035	B
Vest4		0.24
MutPred		0.54		Gain of methylation at N508 (P = 0.0204)
MVP		0.33
MPC		1.1
ClinPred		0.12	T
GERP RS		-0.39
Varity_R		0.13
gMVP		0.62
Mutation Taster		=81/19	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: rs776023291; hg19: chrX-110491181;