rs727503839

Variant names:

• chr15-42402956-G-C
• rs727503839
• NM_000070.3:c.1699G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-42402956-G-C
• chr15-42402956-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP3_Strong

The NM_000070.3(CAPN3):​c.1699G>C​(p.Gly567Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G567W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06
• Publications: 0 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000070.3 (CAPN3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 4081603
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42402956-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 166791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1699G>C	p.Gly567Arg	missense_variant	Exon 13 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1699G>C	p.Gly567Arg	missense_variant	Exon 13 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1555G>C	p.Gly519Arg	missense_variant	Exon 12 of 21		NP_775110.1
CAPN3	NM_173088.2	c.163G>C	p.Gly55Arg	missense_variant	Exon 2 of 13		NP_775111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1699G>C	p.Gly567Arg	missense_variant	Exon 13 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*2153G>C		non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2153G>C		3_prime_UTR_variant	Exon 16 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;.;.;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	.;M;.;M;.;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	.;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.023	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.
Vest4		0.96
MutPred		0.88		.;Gain of disorder (P = 0.0348);.;Gain of disorder (P = 0.0348);.;.;
MVP		0.97
MPC		0.69
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.10	Neutral
Varity_R		0.86
gMVP		0.91
Mutation Taster		=0/100	disease causing

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: rs727503839; hg19: chr15-42695154;