rs35495899

Variant names:

• chr17-50175393-C-T
• rs35495899
• NM_000023.4:c.1120C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-50175393-C-T
• chr17-50175393-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.1120C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 374, p.(Arg374Cys). The filtering allele frequency of this variant for gnomAD v4.1.0 exomes is 0.01775 (the lower threshold of the 95% CI of 63/33478 African/African American chromosomes), which is higher than the ClinGen LGMD VCEP threshold (>0.002) for BA1, and therefore meets this criterion (BA1). This variant is not located in a splice region, and the SpliceAI score is 0, which suggests it does not impact splicing. The computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on SGCA function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180427/MONDO:0015152/189

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (4 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 1.25
• Publications: 1 publications found

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

ENSG00000253730 (HGNC:):

ACMG classification

Specifications for SGCA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.1120C>T	p.Arg374Cys	missense	Exon 9 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.748C>T	p.Arg250Cys	missense	Exon 7 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.947C>T		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.1120C>T	p.Arg374Cys	missense	Exon 9 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.748C>T	p.Arg250Cys	missense	Exon 7 of 8	ENSP00000345522.6	Q16586-2
	ENSG00000253730	ENST00000504307.4	TSL:1	n.548-3216G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152274 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.000103

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00171 AC: 424 AN: 248192 AF XY: 0.00131

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000658 AC: 961 AN: 1460732 Hom.: 4 Cov.: 31 AF XY: 0.000590 AC XY: 429 AN XY: 726698

African (AFR) AF: 0.0190 AC: 635 AN: 33478

American (AMR) AF: 0.00224 AC: 100 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86232

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52368

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111982

Other (OTH) AF: 0.00159 AC: 96 AN: 60368

GnomAD4 genome AF: 0.00523 AC: 797 AN: 152392 Hom.: 5 Cov.: 33 AF XY: 0.00503 AC XY: 375 AN XY: 74516

African (AFR) AF: 0.0175 AC: 727 AN: 41594

American (AMR) AF: 0.00346 AC: 53 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68044

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00233 Hom.: 4

Bravo AF: 0.00602

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00201 AC: 244

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal recessive limb-girdle muscular dystrophy type 2D (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.028	D
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.90
MPC		0.48
ClinPred		0.0062	T
GERP RS		1.3
Varity_R		0.078
gMVP		0.21
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs35495899; hg19: chr17-48252754;