rs1801449

Variant names:

• chr15-42389001-G-A
• rs1801449
• NM_000070.3:c.706G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000070.3(CAPN3):​c.706G>A​(p.Ala236Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0836 in 1,613,710 control chromosomes in the GnomAD database, including 19,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A236A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (8667 hom., cov: 31)
  • Exomes 𝑓: 0.069 (10430 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 5.24
• Publications: 30 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000070.3
• BP4: Computational evidence support a benign effect (MetaRNN=3.6192458E-5).
• BP6: Variant 15-42389001-G-A is Benign according to our data. Variant chr15-42389001-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 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.706G>A	p.Ala236Thr	missense	Exon 5 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.706G>A	p.Ala236Thr	missense	Exon 5 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.706G>A	p.Ala236Thr	missense	Exon 5 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.706G>A	p.Ala236Thr	missense	Exon 5 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.706G>A	p.Ala236Thr	missense	Exon 5 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.706G>A	p.Ala236Thr	missense	Exon 5 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33668 AN: 151864 Hom.: 8632 Cov.: 31

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.113 AC: 28526 AN: 251464 AF XY: 0.106

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.0946

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0836

GnomAD4 exome AF: 0.0692 AC: 101133 AN: 1461728 Hom.: 10430 Cov.: 32 AF XY: 0.0698 AC XY: 50733 AN XY: 727158

African (AFR) AF: 0.651 AC: 21794 AN: 33470

American (AMR) AF: 0.0779 AC: 3485 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2776 AN: 26134

East Asian (EAS) AF: 0.112 AC: 4431 AN: 39700

South Asian (SAS) AF: 0.138 AC: 11891 AN: 86248

European-Finnish (FIN) AF: 0.0950 AC: 5073 AN: 53420

Middle Eastern (MID) AF: 0.109 AC: 630 AN: 5756

European-Non Finnish (NFE) AF: 0.0404 AC: 44955 AN: 1111888

Other (OTH) AF: 0.101 AC: 6098 AN: 60390

GnomAD4 genome AF: 0.222 AC: 33763 AN: 151982 Hom.: 8667 Cov.: 31 AF XY: 0.219 AC XY: 16236 AN XY: 74296

African (AFR) AF: 0.630 AC: 26078 AN: 41362

American (AMR) AF: 0.0986 AC: 1507 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3470

East Asian (EAS) AF: 0.118 AC: 606 AN: 5150

South Asian (SAS) AF: 0.136 AC: 654 AN: 4826

European-Finnish (FIN) AF: 0.0960 AC: 1016 AN: 10586

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3162 AN: 67984

Other (OTH) AF: 0.167 AC: 353 AN: 2114

Alfa AF: 0.0975 Hom.: 11262

Bravo AF: 0.241

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0376 AC: 145

ESP6500AA AF: 0.621 AC: 2737

ESP6500EA AF: 0.0497 AC: 427

ExAC AF: 0.124 AC: 15028

Asia WGS AF: 0.143 AC: 497 AN: 3476

EpiCase AF: 0.0481

EpiControl AF: 0.0458

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Autosomal recessive limb-girdle muscular dystrophy type 2A (6)
-	-	2	not provided (2)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.000036	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.14
ClinPred		0.013	T
GERP RS		5.4
Varity_R		0.56
gMVP		0.51
Mutation Taster		=100/0	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: rs1801449; hg19: chr15-42681199; COSMIC: COSV58820420;