rs1801496

Variant names:

• chr15-42359901-T-C
• rs1801496
• NM_000070.3:c.96T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-42359901-T-C
• chr15-42359901-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000070.3(CAPN3):​c.96T>C​(p.Thr32Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0872 in 1,614,140 control chromosomes in the GnomAD database, including 7,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene CAPN3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.097 (840 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6509 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -4.53
• Publications: 9 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

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

ENSG00000258461 (HGNC:):

ACMG classification

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 15-42359901-T-C is Benign according to our data. Variant chr15-42359901-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.96T>C	p.Thr32Thr	synonymous	Exon 1 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.0966 AC: 14703 AN: 152162 Hom.: 830 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0714

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0946

GnomAD2 exomes AF: 0.0911 AC: 22885 AN: 251334 AF XY: 0.0985

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.0794

Gnomad OTH exome AF: 0.0939

GnomAD4 exome AF: 0.0862 AC: 126073 AN: 1461860 Hom.: 6509 Cov.: 33 AF XY: 0.0901 AC XY: 65555 AN XY: 727230

African (AFR) AF: 0.133 AC: 4452 AN: 33478

American (AMR) AF: 0.0490 AC: 2192 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3265 AN: 26134

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39700

South Asian (SAS) AF: 0.197 AC: 16999 AN: 86258

European-Finnish (FIN) AF: 0.101 AC: 5384 AN: 53414

Middle Eastern (MID) AF: 0.141 AC: 815 AN: 5766

European-Non Finnish (NFE) AF: 0.0785 AC: 87255 AN: 1111992

Other (OTH) AF: 0.0936 AC: 5653 AN: 60396

GnomAD4 genome AF: 0.0968 AC: 14748 AN: 152280 Hom.: 840 Cov.: 32 AF XY: 0.0980 AC XY: 7296 AN XY: 74452

African (AFR) AF: 0.133 AC: 5536 AN: 41546

American (AMR) AF: 0.0713 AC: 1091 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3470

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5190

South Asian (SAS) AF: 0.185 AC: 894 AN: 4828

European-Finnish (FIN) AF: 0.100 AC: 1063 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5448 AN: 68016

Other (OTH) AF: 0.0931 AC: 197 AN: 2116

Alfa AF: 0.0885 Hom.: 354

Bravo AF: 0.0933

Asia WGS AF: 0.0890 AC: 308 AN: 3478

EpiCase AF: 0.0852

EpiControl AF: 0.0855

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Autosomal recessive limb-girdle muscular dystrophy type 2A (4)
-	-	2	not provided (2)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
-	-	1	Myopathy, centronuclear, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.058
DANN	Benign	0.25
PhyloP100		-4.5
PromoterAI		0.0071	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801496; hg19: chr15-42652099;