dbSNP rs35130237: SGCA:p.Arg141Ser (chr17-50168409-C-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000023.4(SGCA):c.421C>A(p.Arg141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,589,732 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign 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. R141H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 4 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:4

Conservation

PhyloP100: 0.159

Publications

4 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, STRONG Submitted by: ClinGen, PanelApp Australia
autosomal recessive limb-girdle muscular dystrophy type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

SGCA links:

ENSG00000253730 (HGNC:):

ENSG00000253730 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 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, 7 uncertain in NM_000023.4

BP4

Computational evidence support a benign effect (MetaRNN=0.016697764).

BP6

Variant 17-50168409-C-A is Benign according to our data. Variant chr17-50168409-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197618.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

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	UniProt
SGCA	NM_000023.4	MANE Select	c.421C>A	p.Arg141Ser	missense	Exon 5 of 10	NP_000014.1	A0A0S2Z4Q1
SGCA	NM_001135697.3		c.421C>A	p.Arg141Ser	missense	Exon 5 of 8	NP_001129169.1	A0A0S2Z4P8
SGCA	NR_135553.2		n.457C>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCA	ENST00000262018.8	TSL:1 MANE Select	c.421C>A	p.Arg141Ser	missense	Exon 5 of 10	ENSP00000262018.3	Q16586-1
SGCA	ENST00000344627.10	TSL:1	c.421C>A	p.Arg141Ser	missense	Exon 5 of 8	ENSP00000345522.6	Q16586-2
SGCA	ENST00000952408.1		c.511C>A	p.Arg171Ser	missense	Exon 5 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000596

AC:

125

AN:

209650

AF XY:

0.000559

show subpopulations

Gnomad AFR exome

AF:

0.0000792

Gnomad AMR exome

AF:

0.000992

Gnomad ASJ exome

AF:

0.000217

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000562

Gnomad NFE exome

AF:

0.000857

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000837

AC:

1203

AN:

1437470

Hom.:

Cov.:

AF XY:

0.000810

AC XY:

577

AN XY:

712550

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33166

American (AMR)

AF:

0.00115

AC:

AN:

41012

Ashkenazi Jewish (ASJ)

AF:

0.000351

AC:

AN:

25614

East Asian (EAS)

AF:

0.00

AC:

AN:

38756

South Asian (SAS)

AF:

0.000243

AC:

AN:

82400

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51292

Middle Eastern (MID)

AF:

0.00248

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.000973

AC:

1071

AN:

1100178

Other (OTH)

AF:

0.000606

AC:

AN:

59410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000585

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41546

American (AMR)

AF:

0.00163

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000765

AC:

AN:

67994

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000751

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000455

AC:

ClinVar

ClinVar submissions

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 (6)

not provided (5)

Cardiomyopathy (1)

Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

1.8

PhyloP100

0.16

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.64

REVEL

Uncertain

0.60

Sift

Benign

0.12

Sift4G

Uncertain

0.057

Polyphen

0.96

Vest4

0.56

MVP

0.94

MPC

0.39

ClinPred

0.016

GERP RS

2.3

Varity_R

0.12

gMVP

0.75

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over