rs767106920

Variant names:

• chr15-42394325-G-A
• rs767106920
• NM_000070.3:c.1099G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000070.3(CAPN3):​c.1099G>A​(p.Gly367Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,408,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G367delinsNKNRC) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 9.63
• Publications: 6 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000070.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 15-42394325-G-A is Pathogenic according to our data. Variant chr15-42394325-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468639.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1099G>A	p.Gly367Ser	missense	Exon 8 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.1099G>A	p.Gly367Ser	missense	Exon 8 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.955G>A	p.Gly319Ser	missense	Exon 7 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1099G>A	p.Gly367Ser	missense	Exon 8 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1099G>A	p.Gly367Ser	missense	Exon 8 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.955G>A	p.Gly319Ser	missense	Exon 7 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000536 AC: 9 AN: 167974 AF XY: 0.0000451

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000811

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000296

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 40 AN: 1408370 Hom.: 0 Cov.: 31 AF XY: 0.0000345 AC XY: 24 AN XY: 695554

African (AFR) AF: 0.00 AC: 0 AN: 32218

American (AMR) AF: 0.0000817 AC: 3 AN: 36706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36600

South Asian (SAS) AF: 0.000288 AC: 23 AN: 79792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1083716

Other (OTH) AF: 0.0000171 AC: 1 AN: 58454

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000345 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	2	-	not provided (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.99
MPC		0.63
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.96
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs767106920; hg19: chr15-42686523; COSMIC: COSV58824883;