rs17599

chr1-223766378-A-Cchr1-223766378-A-Gchr1-223766378-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001748.5(CAPN2):c.1702A>C(p.Lys568Gln) variant causes a missense change. The variant allele was found at a frequency of 0.235 in 1,610,986 control chromosomes in the GnomAD database, including 45,884 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3680 hom., cov: 33)
  • Exomes 𝑓: 0.24 (42204 hom.)
• Consequence: CAPN2 NM_001748.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15

Genes affected

CAPN2 (HGNC:1479): (calpain 2) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 2. Multiple heterogeneous transcriptional start sites in the 5' UTR have been reported. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015718639).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN2	NM_001748.5	c.1702A>C	p.Lys568Gln	missense_variant	16/21	ENST00000295006.6
CAPN2	NM_001146068.2	c.1468A>C	p.Lys490Gln	missense_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6	c.1702A>C	p.Lys568Gln	missense_variant	16/21	1	NM_001748.5	P1
CAPN2	ENST00000433674.6	c.1468A>C	p.Lys490Gln	missense_variant	16/21	2
CAPN2	ENST00000474026.5	n.2031A>C		non_coding_transcript_exon_variant	5/9	2
CAPN2	ENST00000487223.5	n.1429A>C		non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32254 AN: 152092 Hom.: 3679 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.228 AC: 57279 AN: 251362 Hom.: 6874 AF XY: 0.227 AC XY: 30891 AN XY: 135864

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.249

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.238 AC: 346500 AN: 1458776 Hom.: 42204 Cov.: 31 AF XY: 0.236 AC XY: 171480 AN XY: 725910

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.254

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.212 AC: 32265 AN: 152210 Hom.: 3680 Cov.: 33 AF XY: 0.212 AC XY: 15770 AN XY: 74416

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.211

Alfa AF: 0.233 Hom.: 4162

Bravo AF: 0.203

TwinsUK AF: 0.255 AC: 946

ALSPAC AF: 0.251 AC: 969

ESP6500AA AF: 0.126 AC: 554

ESP6500EA AF: 0.245 AC: 2104

ExAC AF: 0.228 AC: 27633

Asia WGS AF: 0.236 AC: 820 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.235

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	8.5e-7	P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.14
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.0070	.;B
Vest4		0.25
MPC		0.30
ClinPred		0.054	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs17599; hg19: chr1-223954080; COSMIC: COSV54334138; COSMIC: COSV54334138;