chr1-223766378-A-C

Variant names:

• chr1-223766378-A-C
• rs17599
• NM_001748.5:c.1702A>C

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 40 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001748.5. 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
	CAPN2	NM_001748.5	MANE Select	c.1702A>C	p.Lys568Gln	missense	Exon 16 of 21	NP_001739.3	P17655-1
	CAPN2	NM_001146068.2		c.1468A>C	p.Lys490Gln	missense	Exon 16 of 21	NP_001139540.1	P17655-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN2	ENST00000295006.6	TSL:1 MANE Select	c.1702A>C	p.Lys568Gln	missense	Exon 16 of 21	ENSP00000295006.5	P17655-1
	CAPN2	ENST00000946743.1		c.1726A>C	p.Lys576Gln	missense	Exon 17 of 22	ENSP00000616802.1
	CAPN2	ENST00000946744.1		c.1723A>C	p.Lys575Gln	missense	Exon 16 of 21	ENSP00000616803.1

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

GnomAD2 exomes AF: 0.228 AC: 57279 AN: 251362 AF XY: 0.227

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 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

African (AFR) AF: 0.117 AC: 3906 AN: 33448

American (AMR) AF: 0.218 AC: 9764 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4184 AN: 26122

East Asian (EAS) AF: 0.254 AC: 10083 AN: 39676

South Asian (SAS) AF: 0.193 AC: 16633 AN: 86196

European-Finnish (FIN) AF: 0.278 AC: 14856 AN: 53392

Middle Eastern (MID) AF: 0.204 AC: 1177 AN: 5762

European-Non Finnish (NFE) AF: 0.245 AC: 272281 AN: 1109198

Other (OTH) AF: 0.226 AC: 13616 AN: 60264

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

African (AFR) AF: 0.124 AC: 5160 AN: 41526

American (AMR) AF: 0.239 AC: 3652 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 568 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1310 AN: 5180

South Asian (SAS) AF: 0.214 AC: 1033 AN: 4828

European-Finnish (FIN) AF: 0.278 AC: 2941 AN: 10598

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16967 AN: 67994

Other (OTH) AF: 0.211 AC: 445 AN: 2114

Alfa AF: 0.230 Hom.: 6168

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 v4.9

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
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Benign	0.037	D
Sift4G	Uncertain	0.056	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
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs17599; hg19: chr1-223954080; COSMIC: COSV54334138; COSMIC: COSV54334138;