rs1801324

Positions:

• chr15-42386282-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000070.3(CAPN3):​c.495C>T​(p.Phe165Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,603,796 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (62 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.84

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 15-42386282-C-T is Benign according to our data. Variant chr15-42386282-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42386282-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.495C>T	p.Phe165Phe	synonymous_variant	3/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.495C>T	p.Phe165Phe	synonymous_variant	3/23		NP_077320.1
CAPN3	NM_173087.2	c.495C>T	p.Phe165Phe	synonymous_variant	3/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.495C>T	p.Phe165Phe	synonymous_variant	3/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*291C>T		non_coding_transcript_exon_variant	7/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723	n.*291C>T		3_prime_UTR_variant	7/23	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00995

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00585 AC: 1470 AN: 251416 Hom.: 14 AF XY: 0.00574 AC XY: 780 AN XY: 135878

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00755 AC: 10962 AN: 1451522 Hom.: 62 Cov.: 27 AF XY: 0.00724 AC XY: 5237 AN XY: 722896

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00919

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00594 AC: 904 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00560 AC XY: 417 AN XY: 74448

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00996

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00904 Hom.: 6

Bravo AF: 0.00657

EpiCase AF: 0.00938

EpiControl AF: 0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CAPN3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.5
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1801324; hg19: chr15-42678480;