rs12013711

Variant names:

• chrX-111251613-C-G
• rs12013711
• NM_014289.4:c.829G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-111251613-C-G
• chrX-111251613-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014289.4(CAPN6):​c.829G>C​(p.Val277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,207,785 control chromosomes in the GnomAD database, including 9,167 homozygotes. There are 20,632 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4485 hom., 5876 hem., cov: 22)
  • Exomes 𝑓: 0.045 (4682 hom. 14756 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.52
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9559777E-5).
• BP6: Variant X-111251613-C-G is Benign according to our data. Variant chrX-111251613-C-G is described in ClinVar as Benign. ClinVar VariationId is 1288617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

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.829G>C	p.Val277Leu	missense	Exon 6 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.829G>C	p.Val277Leu	missense	Exon 6 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.427G>C	p.Val143Leu	missense	Exon 4 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 21791 AN: 111161 Hom.: 4480 Cov.: 22

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.00581

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0194

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.0715 AC: 13119 AN: 183409 AF XY: 0.0542

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.000721

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0452 AC: 49518 AN: 1096571 Hom.: 4682 Cov.: 30 AF XY: 0.0408 AC XY: 14756 AN XY: 362007

African (AFR) AF: 0.638 AC: 16830 AN: 26359

American (AMR) AF: 0.0594 AC: 2092 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 449 AN: 19371

East Asian (EAS) AF: 0.000497 AC: 15 AN: 30203

South Asian (SAS) AF: 0.0108 AC: 583 AN: 54089

European-Finnish (FIN) AF: 0.0151 AC: 611 AN: 40533

Middle Eastern (MID) AF: 0.0930 AC: 384 AN: 4131

European-Non Finnish (NFE) AF: 0.0299 AC: 25153 AN: 840628

Other (OTH) AF: 0.0738 AC: 3401 AN: 46055

GnomAD4 genome AF: 0.196 AC: 21843 AN: 111214 Hom.: 4485 Cov.: 22 AF XY: 0.176 AC XY: 5876 AN XY: 33450

African (AFR) AF: 0.618 AC: 18731 AN: 30305

American (AMR) AF: 0.0981 AC: 1029 AN: 10494

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 51 AN: 2632

East Asian (EAS) AF: 0.00141 AC: 5 AN: 3553

South Asian (SAS) AF: 0.0102 AC: 27 AN: 2637

European-Finnish (FIN) AF: 0.0123 AC: 75 AN: 6083

Middle Eastern (MID) AF: 0.123 AC: 27 AN: 219

European-Non Finnish (NFE) AF: 0.0310 AC: 1645 AN: 53103

Other (OTH) AF: 0.166 AC: 249 AN: 1500

Alfa AF: 0.0565 Hom.: 1620

Bravo AF: 0.225

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0294 AC: 85

ESP6500AA AF: 0.611 AC: 2345

ESP6500EA AF: 0.0314 AC: 211

ExAC AF: 0.0772 AC: 9379

EpiCase AF: 0.0317

EpiControl AF: 0.0327

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.51
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.000020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.78	N
PhyloP100		2.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.069
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)
MPC		0.44
ClinPred		0.0045	T
GERP RS		5.3
Varity_R		0.068
gMVP		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs12013711; hg19: chrX-110494841; COSMIC: COSV60695463;