rs193921059

Variant names:

• chrX-111246746-C-T
• rs193921059
• NM_014289.4:c.1757G>A
• CAPN6 p.Arg586Gln

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.1757G>A​(p.Arg586Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,095,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000021 (0 hom. 7 hem.)
• Consequence: CAPN6 NM_014289.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.635
• Publications: 1 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=0.09811187).
• BS2: High Hemizygotes in GnomAdExome4 at 7 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.1757G>A	p.Arg586Gln	missense	Exon 13 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.1757G>A	p.Arg586Gln	missense	Exon 13 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.1355G>A	p.Arg452Gln	missense	Exon 11 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000224 AC: 4 AN: 178613 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 23 AN: 1095510 Hom.: 0 Cov.: 29 AF XY: 0.0000194 AC XY: 7 AN XY: 361028

African (AFR) AF: 0.0000379 AC: 1 AN: 26370

American (AMR) AF: 0.00 AC: 0 AN: 35006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19296

East Asian (EAS) AF: 0.0000994 AC: 3 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 53531

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841124

Other (OTH) AF: 0.0000217 AC: 1 AN: 46012

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.64
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.086
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Varity_R		0.088
gMVP		0.48
Mutation Taster		=85/15	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs193921059;

hg19: chrX-110489974;

COSMIC: COSV60695271;