rs780264754

Variant names:

• chr17-50168390-C-A
• rs780264754
• NM_000023.4:c.402C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-50168390-C-A
• chr17-50168390-C-G
• chr17-50168390-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000262018.8(SGCA):​c.402C>A​(p.Tyr134*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y134Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCA ENST00000262018.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.02
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50168390-C-A is Pathogenic according to our data. Variant chr17-50168390-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1068550.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262018.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.402C>A	p.Tyr134*	stop_gained	Exon 5 of 10	NP_000014.1
	SGCA	NM_001135697.3		c.402C>A	p.Tyr134*	stop_gained	Exon 5 of 8	NP_001129169.1
	SGCA	NR_135553.2		n.438C>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.402C>A	p.Tyr134*	stop_gained	Exon 5 of 10	ENSP00000262018.3
	SGCA	ENST00000344627.10	TSL:1	c.402C>A	p.Tyr134*	stop_gained	Exon 5 of 8	ENSP00000345522.6
	SGCA	ENST00000682109.1		c.282C>A	p.Tyr94*	stop_gained	Exon 4 of 8	ENSP00000508041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 708506

African (AFR) AF: 0.00 AC: 0 AN: 33014

American (AMR) AF: 0.00 AC: 0 AN: 39880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.00 AC: 0 AN: 81694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096478

Other (OTH) AF: 0.00 AC: 0 AN: 59196

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		1.0
Vest4		0.73
GERP RS		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs780264754; hg19: chr17-48245751;