NM_005186.4:c.200G>A

Variant names:

• chr11-65182901-G-A
• rs765955979
• NM_005186.4:c.200G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005186.4(CAPN1):​c.200G>A​(p.Ser67Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,457,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66

Genes affected

CAPN1 (HGNC:1476): (calpain 1) 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 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Calpain catalytic (size 299) in uniprot entity CAN1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_005186.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.200G>A	p.Ser67Asn	missense_variant	Exon 2 of 22	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.200G>A	p.Ser67Asn	missense_variant	Exon 2 of 22	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457016 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000317 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;D;D;D;D;D;D;D;D;.;D;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;.;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;H;H;H;.;.;.;.;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.98	.;.;D;.;.;D;D;D;.;.;.;.;D
Vest4		0.51, 0.51, 0.51, 0.52, 0.45
MVP		0.94
MPC		0.97
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.87
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs765955979; hg19: chr11-64950372;