11-65182922-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_005186.4(CAPN1):c.221G>A(p.Gly74Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00033 in 1,612,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.73

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21250153).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000332 (485/1460038) while in subpopulation MID AF= 0.00295 (17/5762). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4_exome. There are 269 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN1	NM_005186.4	c.221G>A	p.Gly74Asp	missense_variant	2/22	ENST00000279247.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN1	ENST00000279247.11	c.221G>A	p.Gly74Asp	missense_variant	2/22	1	NM_005186.4	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000330 AC: 81 AN: 245290 Hom.: 0 AF XY: 0.000383 AC XY: 51 AN XY: 133134

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000695

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000332 AC: 485 AN: 1460038 Hom.: 0 Cov.: 31 AF XY: 0.000370 AC XY: 269 AN XY: 726152

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000512

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74444

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000719 AC: 6

ExAC AF: 0.000323 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive spastic paraplegia type 76 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 76 (MIM#616907). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated peptidase C2 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been reported as likely pathogenic in one compound heterozygous individual with hereditary spastic paraplegia, however the variant was in cis with another missense that was also considered to be likely pathogenic (LOVD, PMID: 28566166). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 22, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the CAPN1 protein (p.Gly74Asp). This variant is present in population databases (rs201318945, gnomAD 0.07%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 28566166). ClinVar contains an entry for this variant (Variation ID: 1510947). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;D;T;T;D;D;D;T;.;T;.;D
Eigen	Benign	0.093
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;.;.;.;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.030	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;D;D;D;.;.;.;.;D
Vest4		0.55, 0.55, 0.55, 0.51
MVP		0.70
MPC		1.2
ClinPred		0.61	D
GERP RS		4.2
Varity_R		0.93
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201318945; hg19: chr11-64950393;