Genetic Variant SGCA:p.Thr176Thr (chr17-50168516-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000023.4(SGCA):c.528C>T(p.Thr176Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,580,106 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 28 hom. )

Consequence

SGCA
NM_000023.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.242

Publications

3 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 17-50168516-C-T is Benign according to our data. Variant chr17-50168516-C-T is described in ClinVar as Benign. ClinVar VariationId is 130293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.242 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00863 (1314/152270) while in subpopulation AFR AF = 0.028 (1163/41550). AF 95% confidence interval is 0.0267. There are 17 homozygotes in GnomAd4. There are 653 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 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
SGCA	NM_000023.4	MANE Select	c.528C>T	p.Thr176Thr	synonymous	Exon 5 of 10	NP_000014.1
SGCA	NM_001135697.3		c.528C>T	p.Thr176Thr	synonymous	Exon 5 of 8	NP_001129169.1
SGCA	NR_135553.2		n.564C>T		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.528C>T	p.Thr176Thr	synonymous	Exon 5 of 10	ENSP00000262018.3
SGCA	ENST00000344627.10	TSL:1	c.528C>T	p.Thr176Thr	synonymous	Exon 5 of 8	ENSP00000345522.6
SGCA	ENST00000952408.1		c.618C>T	p.Thr206Thr	synonymous	Exon 5 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes

AF:

0.00855

AC:

1301

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00926

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00277

AC:

541

AN:

194982

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00669

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000407

Gnomad OTH exome

AF:

0.00219

GnomAD4 exome

AF:

0.00134

AC:

1909

AN:

1427836

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

875

AN XY:

706898

show subpopulations

African (AFR)

AF:

0.0296

AC:

975

AN:

32910

American (AMR)

AF:

0.00211

AC:

AN:

39370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25476

East Asian (EAS)

AF:

0.00785

AC:

300

AN:

38226

South Asian (SAS)

AF:

0.000429

AC:

AN:

81512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51016

Middle Eastern (MID)

AF:

0.00436

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000251

AC:

275

AN:

1094466

Other (OTH)

AF:

0.00365

AC:

216

AN:

59120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

122

243

365

486

608

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:

0.00863

AC:

1314

AN:

152270

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

653

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0280

AC:

1163

AN:

41550

American (AMR)

AF:

0.00372

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00909

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68006

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00447

Hom.:

Bravo

AF:

0.00941

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2D (3)

not specified (3)

not provided (2)

Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.3

(source)

DANN

Benign

0.87

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism

(source)

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

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