rs35495899

Positions:

• chr17-50175393-C-G
• chr17-50175393-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000023.4(SGCA):​c.1120C>G​(p.Arg374Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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]

H1-9P (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50175393-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.14378905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.1120C>G	p.Arg374Gly	missense_variant	9/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.748C>G	p.Arg250Gly	missense_variant	7/8		NP_001129169.1
SGCA	NR_135553.2	n.947C>G		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.1120C>G	p.Arg374Gly	missense_variant	9/10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.11	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.039	B;B
Vest4		0.24
MutPred		0.36		.;Gain of catalytic residue at V375 (P = 0.0509);
MVP		0.92
MPC		0.66
ClinPred		0.091	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35495899; hg19: chr17-48252754;