rs769250018

Variant names:

• chr5-156647520-C-A
• rs769250018
• NM_000337.6:c.559C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-156647520-C-A
• chr5-156647520-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000337.6(SGCD):​c.559C>A​(p.Pro187Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P187S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCD NM_000337.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

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]

SGCD Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	NM_000337.6	c.559C>A	p.Pro187Thr	missense_variant	Exon 7 of 9	ENST00000337851.9	NP_000328.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000337851.9	c.559C>A	p.Pro187Thr	missense_variant	Exon 7 of 9	1	NM_000337.6	ENSP00000338343.4
SGCD	ENST00000435422.7	c.556C>A	p.Pro186Thr	missense_variant	Exon 6 of 8	1		ENSP00000403003.2
SGCD	ENST00000517913.5	c.559C>A	p.Pro187Thr	missense_variant	Exon 9 of 10	5		ENSP00000429378.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427954 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 706848

African (AFR) AF: 0.00 AC: 0 AN: 32934

American (AMR) AF: 0.00 AC: 0 AN: 40112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 38584

South Asian (SAS) AF: 0.00 AC: 0 AN: 81702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092776

Other (OTH) AF: 0.00 AC: 0 AN: 59192

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P187T variant (also known as c.559C>A), located in coding exon 6 of the SGCD gene, results from a C to A substitution at nucleotide position 559. The proline at codon 187 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.0	.;M;.
PhyloP100		5.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.54
MutPred		0.67		.;Gain of phosphorylation at P186 (P = 0.0292);.;
MVP		0.97
MPC		0.58
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.38
gMVP		0.64
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs769250018; hg19: chr5-156074530; COSMIC: COSV61908333;