11-65182890-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_005186.4(CAPN1):c.189G>C(p.Pro63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,606,204 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P63P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CAPN1 NM_005186.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.01

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 Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-65182890-G-C is Benign according to our data. Variant chr11-65182890-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2080717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN1	NM_005186.4	c.189G>C	p.Pro63=	synonymous_variant	2/22	ENST00000279247.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN1	ENST00000279247.11	c.189G>C	p.Pro63=	synonymous_variant	2/22	1	NM_005186.4	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000402 AC: 94 AN: 233884 Hom.: 0 AF XY: 0.000402 AC XY: 51 AN XY: 126950

Gnomad AFR exome AF: 0.000218

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000693

Gnomad FIN exome AF: 0.000675

Gnomad NFE exome AF: 0.000692

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000334 AC: 486 AN: 1454122 Hom.: 0 Cov.: 31 AF XY: 0.000343 AC XY: 248 AN XY: 722698

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000943

Gnomad4 FIN exome AF: 0.000889

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000751 Hom.: 0

Bravo AF: 0.000230

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CAPN1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.11
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs201613582; hg19: chr11-64950361;