NM_000070.3:c.606T>C

Variant names:

• chr15-42387860-T-C
• rs17593
• NM_000070.3:c.606T>C

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.606T>C​(p.Ser202Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,942 control chromosomes in the GnomAD database, including 1,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (587 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (543 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.00
• 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):

• 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-42387860-T-C is Benign according to our data. Variant chr15-42387860-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 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.606T>C	p.Ser202Ser	synonymous	Exon 4 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.606T>C	p.Ser202Ser	synonymous	Exon 4 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.606T>C	p.Ser202Ser	synonymous	Exon 4 of 21	NP_775110.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.606T>C	p.Ser202Ser	synonymous	Exon 4 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.606T>C	p.Ser202Ser	synonymous	Exon 4 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.606T>C	p.Ser202Ser	synonymous	Exon 4 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7548 AN: 151994 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.0388

GnomAD2 exomes AF: 0.0180 AC: 4535 AN: 251450 AF XY: 0.0162

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00856 AC: 12515 AN: 1461830 Hom.: 543 Cov.: 32 AF XY: 0.00871 AC XY: 6332 AN XY: 727204

African (AFR) AF: 0.166 AC: 5546 AN: 33476

American (AMR) AF: 0.0121 AC: 543 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 719 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0226 AC: 1950 AN: 86256

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.0322 AC: 186 AN: 5768

European-Non Finnish (NFE) AF: 0.00227 AC: 2526 AN: 1111960

Other (OTH) AF: 0.0171 AC: 1033 AN: 60394

GnomAD4 genome AF: 0.0499 AC: 7591 AN: 152112 Hom.: 587 Cov.: 32 AF XY: 0.0479 AC XY: 3561 AN XY: 74360

African (AFR) AF: 0.162 AC: 6737 AN: 41504

American (AMR) AF: 0.0223 AC: 341 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4820

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 67994

Other (OTH) AF: 0.0384 AC: 81 AN: 2108

Alfa AF: 0.0272 Hom.: 499

Bravo AF: 0.0561

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00498

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	-	2	not provided (2)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-1.0
Mutation Taster		=93/7	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: rs17593; hg19: chr15-42680058;