rs759767804

chr5-156595010-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000337.6(SGCD):c.461A>G(p.Asn154Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SGCD NM_000337.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16015697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCD	NM_000337.6	c.461A>G	p.Asn154Ser	missense_variant	6/9	ENST00000337851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000337851.9	c.461A>G	p.Asn154Ser	missense_variant	6/9	1	NM_000337.6	P4
SGCD	ENST00000435422.7	c.458A>G	p.Asn153Ser	missense_variant	5/8	1		A1
SGCD	ENST00000517913.5	c.461A>G	p.Asn154Ser	missense_variant	8/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247914 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460094 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Invitae

Jun 13, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 154 of the SGCD protein (p.Asn154Ser). This variant is present in population databases (rs759767804, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 532693). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.15
MutPred		0.37		.;Loss of catalytic residue at N153 (P = 0.0257);.;
MVP		0.79
MPC		0.096
ClinPred		0.30	T
GERP RS		4.5
Varity_R		0.060
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759767804; hg19: chr5-156022020;