Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000023.4(SGCA):c.541C>A(p.Arg181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,575,936 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. R181H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 2.53

Publications

1 publications found

Variant links:

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA 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 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

SGCA links:

ENSG00000253730 (HGNC:):

ENSG00000253730 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000023.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 17-50168529-C-A is Pathogenic according to our data. Variant chr17-50168529-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288595.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000023.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SGCA	NM_000023.4	MANE Select	c.541C>A	p.Arg181Ser	missense	Exon 5 of 10	NP_000014.1
SGCA	NM_001135697.3		c.541C>A	p.Arg181Ser	missense	Exon 5 of 8	NP_001129169.1
SGCA	NR_135553.2		n.577C>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SGCA	ENST00000262018.8	TSL:1 MANE Select	c.541C>A	p.Arg181Ser	missense	Exon 5 of 10	ENSP00000262018.3
SGCA	ENST00000344627.10	TSL:1	c.541C>A	p.Arg181Ser	missense	Exon 5 of 8	ENSP00000345522.6
SGCA	ENST00000682109.1		c.421C>A	p.Arg141Ser	missense	Exon 4 of 8	ENSP00000508041.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

187924

AF XY:

0.0000199

show subpopulations

Gnomad AFR exome

AF:

0.000177

Gnomad AMR exome

AF:

0.0000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000632

AC:

AN:

1423802

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704482

show subpopulations

African (AFR)

AF:

0.000183

AC:

AN:

32820

American (AMR)

AF:

0.0000773

AC:

AN:

38832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25428

East Asian (EAS)

AF:

0.00

AC:

AN:

37984

South Asian (SAS)

AF:

0.00

AC:

AN:

81122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092110

Other (OTH)

AF:

0.00

AC:

AN:

58974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000307

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.00000834

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2D (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

0.11

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.6

PhyloP100

2.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.79

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.77

MutPred

0.83

Loss of methylation at R181 (P = 0.0124)

MVP

0.99

MPC

0.81

ClinPred

0.42

GERP RS

3.6

Varity_R

0.37

gMVP

0.89

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs574376340

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over