rs1023858527

Variant names:

• chrX-111248579-C-G
• rs1023858527
• NM_014289.4:c.1474G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014289.4(CAPN6):​c.1474G>C​(p.Val492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,204,575 control chromosomes in the GnomAD database, including 1 homozygotes. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.0000092 (1 hom. 1 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.344
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07486606).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

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.1474G>C	p.Val492Leu	missense	Exon 10 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.1474G>C	p.Val492Leu	missense	Exon 10 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.1072G>C	p.Val358Leu	missense	Exon 8 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111911 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

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: 0.00

Gnomad OTH AF: 0.00133

GnomAD4 exome AF: 0.00000915 AC: 10 AN: 1092664 Hom.: 1 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 359178

African (AFR) AF: 0.00 AC: 0 AN: 26273

American (AMR) AF: 0.000199 AC: 7 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2896

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838527

Other (OTH) AF: 0.0000655 AC: 3 AN: 45829

GnomAD4 genome AF: 0.000116 AC: 13 AN: 111911 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34095

African (AFR) AF: 0.00 AC: 0 AN: 30760

American (AMR) AF: 0.00104 AC: 11 AN: 10588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53206

Other (OTH) AF: 0.00133 AC: 2 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000298

ClinVar

ClinVar submissions

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	Benign	0.21
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.092	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.58	N
PhyloP100		0.34
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.10
MutPred		0.56		Gain of sheet (P = 0.1945)
MVP		0.44
MPC		0.44
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.82
Mutation Taster		=84/16	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: rs1023858527; hg19: chrX-110491807;