17-50169187-C-T

Variant names:

• chr17-50169187-C-T
• rs201131924
• NM_000023.4:c.680C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000023.4(SGCA):​c.680C>T​(p.Pro227Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 108 pathogenic changes around while only 2 benign (98%) in NM_000023.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4154927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4	c.680C>T	p.Pro227Leu	missense_variant	Exon 6 of 10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.584+615C>T		intron_variant	Intron 5 of 7		NP_001129169.1
SGCA	NR_135553.2	n.716C>T		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.680C>T	p.Pro227Leu	missense_variant	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.53
Sift	Benign	0.090	T
Sift4G	Benign	0.13	T
Polyphen		0.55	P
Vest4		0.42
MutPred		0.54		Loss of disorder (P = 0.0411);
MVP		1.0
MPC		0.48
ClinPred		0.70	D
GERP RS		4.1
Varity_R		0.064
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201131924; hg19: chr17-48246548;