rs1801324

Variant names:

• chr15-42386282-C-T
• rs1801324
• NM_000070.3:c.495C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 166785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.495C>T	p.Phe165Phe	synonymous	Exon 3 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.495C>T	p.Phe165Phe	synonymous	Exon 3 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.495C>T	p.Phe165Phe	synonymous	Exon 3 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.495C>T	p.Phe165Phe	synonymous	Exon 3 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.495C>T	p.Phe165Phe	synonymous	Exon 3 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.495C>T	p.Phe165Phe	synonymous	Exon 3 of 21	ENSP00000183936.4	P20807-2

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

GnomAD2 exomes AF: 0.00585 AC: 1470 AN: 251416 AF XY: 0.00574

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 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

African (AFR) AF: 0.00132 AC: 44 AN: 33286

American (AMR) AF: 0.00456 AC: 204 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26066

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86038

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53400

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5748

European-Non Finnish (NFE) AF: 0.00919 AC: 10133 AN: 1102572

Other (OTH) AF: 0.00656 AC: 394 AN: 60044

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

African (AFR) AF: 0.00178 AC: 74 AN: 41570

American (AMR) AF: 0.00778 AC: 119 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00996 AC: 677 AN: 68006

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00824 Hom.: 8

Bravo AF: 0.00657

EpiCase AF: 0.00938

EpiControl AF: 0.00853

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2A (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.5
DANN	Benign	0.87
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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: rs1801324; hg19: chr15-42678480;