rs1421460814

Positions:

• chr5-156508693-G-C
• chr5-156508693-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000337.6(SGCD):​c.285G>C​(p.Gln95His) 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. 16/21 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: SGCD NM_000337.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27879405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCD	NM_000337.6	c.285G>C	p.Gln95His	missense_variant	4/9	ENST00000337851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000337851.9	c.285G>C	p.Gln95His	missense_variant	4/9	1	NM_000337.6	P4
SGCD	ENST00000435422.7	c.282G>C	p.Gln94His	missense_variant	3/8	1		A1
SGCD	ENST00000517913.5	c.285G>C	p.Gln95His	missense_variant	6/10	5
SGCD	ENST00000524347.2	c.*149G>C		3_prime_UTR_variant, NMD_transcript_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SGCD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 95 of the SGCD protein (p.Gln95His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.28
DEOGEN2	Uncertain	0.50	.;D;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0014
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.14	.;N;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.45	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.76	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.43	B;P;P
Vest4		0.35
MutPred		0.30		.;Loss of ubiquitination at K91 (P = 0.1486);.;
MVP		0.83
MPC		0.16
ClinPred		0.45	T
GERP RS		3.7
Varity_R		0.042
gMVP		0.51

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: rs1421460814; hg19: chr5-155935703;