chr17-50170328-C-T

Variant names:

• chr17-50170328-C-T
• rs1801191
• NM_000023.4:c.933C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000023.4(SGCA):​c.933C>T​(p.Val311Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 1,613,718 control chromosomes in the GnomAD database, including 2,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (935 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2020 hom.)
• Consequence: SGCA NM_000023.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.90
• Publications: 8 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 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

ENSG00000253730 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.284).
• BP6: Variant 17-50170328-C-T is Benign according to our data. Variant chr17-50170328-C-T is described in ClinVar as Benign. ClinVar VariationId is 130294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

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.933C>T	p.Val311Val	synonymous	Exon 7 of 10	NP_000014.1
	SGCA	NM_001135697.3		c.585-312C>T		intron	N/A	NP_001129169.1
	SGCA	NR_135553.2		n.784-312C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.933C>T	p.Val311Val	synonymous	Exon 7 of 10	ENSP00000262018.3
	SGCA	ENST00000344627.10	TSL:1	c.585-312C>T		intron	N/A	ENSP00000345522.6
	SGCA	ENST00000952408.1		c.1023C>T	p.Val341Val	synonymous	Exon 7 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12771 AN: 152128 Hom.: 930 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00962

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0704

GnomAD2 exomes AF: 0.0422 AC: 10614 AN: 251264 AF XY: 0.0384

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.00712

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0398

GnomAD4 exome AF: 0.0430 AC: 62890 AN: 1461472 Hom.: 2020 Cov.: 31 AF XY: 0.0414 AC XY: 30066 AN XY: 726962

African (AFR) AF: 0.211 AC: 7062 AN: 33464

American (AMR) AF: 0.0306 AC: 1369 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 1215 AN: 26130

East Asian (EAS) AF: 0.00796 AC: 316 AN: 39692

South Asian (SAS) AF: 0.0107 AC: 926 AN: 86256

European-Finnish (FIN) AF: 0.0331 AC: 1769 AN: 53400

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5768

European-Non Finnish (NFE) AF: 0.0424 AC: 47170 AN: 1111654

Other (OTH) AF: 0.0480 AC: 2898 AN: 60388

GnomAD4 genome AF: 0.0840 AC: 12795 AN: 152246 Hom.: 935 Cov.: 32 AF XY: 0.0812 AC XY: 6047 AN XY: 74448

African (AFR) AF: 0.203 AC: 8445 AN: 41506

American (AMR) AF: 0.0461 AC: 706 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.00944 AC: 49 AN: 5188

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4826

European-Finnish (FIN) AF: 0.0358 AC: 380 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2838 AN: 68026

Other (OTH) AF: 0.0697 AC: 147 AN: 2110

Alfa AF: 0.0516 Hom.: 464

Bravo AF: 0.0906

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0377

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2D (2)
-	-	2	not provided (2)
-	-	1	Dystrophin deficiency (1)
-	-	1	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1801191; hg19: chr17-48247689;