rs1555417328

Variant names:

• chr15-42360040-G-C
• rs1555417328
• NM_000070.3:c.235G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000070.3(CAPN3):​c.235G>C​(p.Glu79Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.96
• 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):

• 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: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage

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.235G>C	p.Glu79Gln	missense	Exon 1 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.235G>C	p.Glu79Gln	missense	Exon 1 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.235G>C	p.Glu79Gln	missense	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.235G>C	p.Glu79Gln	missense	Exon 1 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.235G>C	p.Glu79Gln	missense	Exon 1 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.235G>C	p.Glu79Gln	missense	Exon 1 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.43
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.14	B
Vest4		0.20
MutPred		0.76		Loss of solvent accessibility (P = 0.0721)
MVP		0.92
MPC		0.23
ClinPred		0.41	T
GERP RS		6.0
PromoterAI		-0.015	Neutral
Varity_R		0.45
gMVP		0.55
Mutation Taster		=1/99	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: rs1555417328; hg19: chr15-42652238;