NM_005186.4:c.1442G>A

Variant names:

• chr11-65206551-G-A
• rs763471308
• NM_005186.4:c.1442G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005186.4(CAPN1):​c.1442G>A​(p.Arg481Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89
• Publications: 4 publications found

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]

CAPN1 Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 76

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN1	NM_005186.4	MANE Select	c.1442G>A	p.Arg481Gln	missense	Exon 13 of 22	NP_005177.2
	CAPN1	NM_001198868.2		c.1442G>A	p.Arg481Gln	missense	Exon 13 of 22	NP_001185797.1
	CAPN1	NM_001198869.2		c.1442G>A	p.Arg481Gln	missense	Exon 13 of 22	NP_001185798.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN1	ENST00000279247.11	TSL:1 MANE Select	c.1442G>A	p.Arg481Gln	missense	Exon 13 of 22	ENSP00000279247.7
	CAPN1	ENST00000524773.5	TSL:1	c.1442G>A	p.Arg481Gln	missense	Exon 13 of 22	ENSP00000434176.1
	CAPN1	ENST00000527323.5	TSL:1	c.1442G>A	p.Arg481Gln	missense	Exon 12 of 21	ENSP00000431984.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461118 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive spastic paraplegia type 76 Uncertain:1

Jun 01, 2018

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.89
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs763471308; hg19: chr11-64974022; COSMIC: COSV54198268; COSMIC: COSV54198268;