X-111248994-G-A

Variant names:

• chrX-111248994-G-A
• rs143524909
• NM_014289.4:c.1222C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014289.4(CAPN6):​c.1222C>T​(p.Arg408Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,208,740 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 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.1222C>T	p.Arg408Cys	missense	Exon 9 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.1222C>T	p.Arg408Cys	missense	Exon 9 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.820C>T	p.Arg274Cys	missense	Exon 7 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111573 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000652

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183271 AF XY: 0.0000443

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097167 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 3 AN XY: 362539

African (AFR) AF: 0.0000379 AC: 1 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841173

Other (OTH) AF: 0.0000434 AC: 2 AN: 46064

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111573 Hom.: 0 Cov.: 23 AF XY: 0.0000592 AC XY: 2 AN XY: 33769

African (AFR) AF: 0.0000652 AC: 2 AN: 30674

American (AMR) AF: 0.00 AC: 0 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5995

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53194

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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	0.30
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.14
MVP		0.98
MPC		1.5
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.93
Mutation Taster		=83/17	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: rs143524909; hg19: chrX-110492222; COSMIC: COSV105188418;