rs144497243

Positions:

• chr13-23279411-C-A
• chr13-23279411-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000231.3(SGCG):​c.438C>A​(p.Asp146Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.0320

Genes affected

SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Gamma-sarcoglycan (size 290) in uniprot entity SGCG_HUMAN there are 28 pathogenic changes around while only 1 benign (97%) in NM_000231.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16366145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCG	NM_000231.3	c.438C>A	p.Asp146Glu	missense_variant	5/8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.438C>A	p.Asp146Glu	missense_variant	5/8	1	NM_000231.3	ENSP00000218867	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 13, 2017

- -

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.64
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Sift4G	Benign	0.47	T
Polyphen		0.0040	B
Vest4		0.23
MutPred		0.34		Gain of methylation at K148 (P = 0.0781);
MVP		0.74
MPC		0.067
ClinPred		0.12	T
GERP RS		-3.3
Varity_R		0.042
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs144497243; hg19: chr13-23853550;