rs1801505

Variant names:

• chr15-42384492-G-A
• rs1801505
• NM_000070.3:c.319G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-42384492-G-A
• chr15-42384492-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000070.3(CAPN3):​c.319G>A​(p.Glu107Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,074 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (82 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.16
• Publications: 21 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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000070.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009398013).
• BP6: Variant 15-42384492-G-A is Benign according to our data. Variant chr15-42384492-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 11 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.319G>A	p.Glu107Lys	missense	Exon 2 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.319G>A	p.Glu107Lys	missense	Exon 2 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.319G>A	p.Glu107Lys	missense	Exon 2 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.319G>A	p.Glu107Lys	missense	Exon 2 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.319G>A	p.Glu107Lys	missense	Exon 2 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.319G>A	p.Glu107Lys	missense	Exon 2 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1022 AN: 152118 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00966

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00853 AC: 2146 AN: 251436 AF XY: 0.00823

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00874 AC: 12767 AN: 1460838 Hom.: 82 Cov.: 30 AF XY: 0.00847 AC XY: 6158 AN XY: 726816

African (AFR) AF: 0.00108 AC: 36 AN: 33464

American (AMR) AF: 0.000962 AC: 43 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26128

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86238

European-Finnish (FIN) AF: 0.0252 AC: 1347 AN: 53380

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00985 AC: 10946 AN: 1111088

Other (OTH) AF: 0.00616 AC: 372 AN: 60368

GnomAD4 genome AF: 0.00671 AC: 1022 AN: 152236 Hom.: 11 Cov.: 32 AF XY: 0.00674 AC XY: 502 AN XY: 74436

African (AFR) AF: 0.00154 AC: 64 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00966 AC: 657 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00774 Hom.: 19

Bravo AF: 0.00481

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.0104 AC: 1266

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.059	D
MutationAssessor	Benign	0.93	L
PhyloP100		4.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.59
Sift	Benign	0.69	T
Sift4G	Benign	0.83	T
Polyphen		0.0060	B
Vest4		0.34
MPC		0.18
ClinPred		0.0092	T
GERP RS		3.6
Varity_R		0.26
gMVP		0.68
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1801505; hg19: chr15-42676690; COSMIC: COSV107376596;