17-50166077-G-A

Position:

• chr17-50166077-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000023.4(SGCA):​c.37G>A​(p.Val13Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SGCA NM_000023.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

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]

LOC105371818 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.37G>A	p.Val13Ile	missense_variant, splice_region_variant	1/10	ENST00000262018.8	NP_000014.1
LOC105371818	XR_934833.3	n.281C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.37G>A	p.Val13Ile	missense_variant, splice_region_variant	1/10	1	NM_000023.4	ENSP00000262018	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Feb 12, 2022

Homozygous missense variation in exon 1 of SGCA gene that result in the amino acid substitution of isoleucine for valine at codon 13 was detected. The p.Val13lle variant has not been reported in the 1000 genome and gnomAD database. The in silico prediction of the variant is benign by PolyPhen-2 ( HumDiv ),LRT,SIFT and MutationTaster2. In summary, the variant meets our criteria to be classified as variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.0034	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;D
Eigen	Benign	0.032
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.17	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.97	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.80	P;B
Vest4		0.13
MutPred		0.58		Loss of catalytic residue at V13 (P = 0.0625);Loss of catalytic residue at V13 (P = 0.0625);
MVP		0.89
MPC		0.28
ClinPred		0.40	T
GERP RS		3.8
Varity_R		0.062
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.77		Position offset: -4
DS_DL_spliceai		0.53		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48243438; COSMIC: COSV56249867; COSMIC: COSV56249867;