15-42411907-C-T

Position:

• chr15-42411907-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000070.3(CAPN3):​c.*134C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,569,722 control chromosomes in the GnomAD database, including 740,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72904 hom., cov: 30)
  • Exomes 𝑓: 0.97 (667213 hom.)
• Consequence: CAPN3 NM_000070.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.982

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-42411907-C-T is Benign according to our data. Variant chr15-42411907-C-T is described in ClinVar as [Benign]. Clinvar id is 286594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42411907-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.*134C>T		3_prime_UTR_variant	24/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.*134C>T		3_prime_UTR_variant	24/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.*134C>T		3_prime_UTR_variant	11/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.*134C>T		3_prime_UTR_variant	11/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.*134C>T		3_prime_UTR_variant	12/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.*134C>T		3_prime_UTR_variant	11/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.*134C>T		3_prime_UTR_variant	11/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*3036C>T		non_coding_transcript_exon_variant	26/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*3036C>T		3_prime_UTR_variant	26/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148836 AN: 152100 Hom.: 72844 Cov.: 30

Gnomad AFR AF: 0.995

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.942

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.967

Gnomad OTH AF: 0.981

GnomAD4 exome AF: 0.970 AC: 1375192 AN: 1417504 Hom.: 667213 Cov.: 49 AF XY: 0.971 AC XY: 680719 AN XY: 701174

Gnomad4 AFR exome AF: 0.996

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 0.940

Gnomad4 NFE exome AF: 0.966

Gnomad4 OTH exome AF: 0.974

GnomAD4 genome AF: 0.979 AC: 148955 AN: 152218 Hom.: 72904 Cov.: 30 AF XY: 0.978 AC XY: 72782 AN XY: 74416

Gnomad4 AFR AF: 0.995

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 0.997

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.967

Gnomad4 OTH AF: 0.982

Alfa AF: 0.973 Hom.: 67845

Bravo AF: 0.983

Asia WGS AF: 0.997 AC: 3469 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2016

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.70

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: rs3098423; hg19: chr15-42704105;