chr13-23203739-A-G

Variant names:

• chr13-23203739-A-G
• rs2137501268
• NM_000231.3:c.45A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000231.3(SGCG):​c.45A>G​(p.Ile15Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I15T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.141
• Publications: 0 publications found

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]

SGCG Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13605133).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000231.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	NM_000231.3	MANE Select	c.45A>G	p.Ile15Met	missense	Exon 2 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.99A>G	p.Ile33Met	missense	Exon 2 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.45A>G	p.Ile15Met	missense	Exon 3 of 9	NP_001365174.1	Q13326

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	ENST00000218867.4	TSL:1 MANE Select	c.45A>G	p.Ile15Met	missense	Exon 2 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.45A>G	p.Ile15Met	missense	Exon 2 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.45A>G	p.Ile15Met	missense	Exon 3 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.0
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.14
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.070
Sift	Benign	0.40	T
Sift4G	Benign	0.28	T
Polyphen		0.26	B
Vest4		0.27
MutPred		0.23		Gain of glycosylation at P18 (P = 0.1593)
MVP		0.81
MPC		0.098
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.055
gMVP		0.46
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2137501268; hg19: chr13-23777878;