NM_000023.4:c.402C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000023.4(SGCA):​c.402C>T​(p.Tyr134Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,582,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SGCA NM_000023.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-50168390-C-T is Benign according to our data. Variant chr17-50168390-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285226.
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.402C>T	p.Tyr134Tyr	synonymous	Exon 5 of 10	NP_000014.1
	SGCA	NM_001135697.3		c.402C>T	p.Tyr134Tyr	synonymous	Exon 5 of 8	NP_001129169.1
	SGCA	NR_135553.2		n.438C>T		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>T	p.Tyr134Tyr	synonymous	Exon 5 of 10	ENSP00000262018.3
	SGCA	ENST00000344627.10	TSL:1	c.402C>T	p.Tyr134Tyr	synonymous	Exon 5 of 8	ENSP00000345522.6
	SGCA	ENST00000952408.1		c.492C>T	p.Tyr164Tyr	synonymous	Exon 5 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 4 AN: 200008 AF XY: 0.0000279

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000687

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000231

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 41 AN: 1430250 Hom.: 0 Cov.: 33 AF XY: 0.0000212 AC XY: 15 AN XY: 708506

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

American (AMR) AF: 0.0000502 AC: 2 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: 0.0000328 AC: 36 AN: 1096478

Other (OTH) AF: 0.0000507 AC: 3 AN: 59196

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.7
DANN	Benign	0.67
PhyloP100		1.0

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

Other links and lift over

dbSNP: rs780264754; hg19: chr17-48245751;