rs267607045

Variant names:

• chr5-156594940-G-C
• rs267607045
• NM_000337.6:c.391G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000337.6(SGCD):​c.391G>C​(p.Ala131Pro) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A131A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCD NM_000337.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.22
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 5-156594940-G-C is Pathogenic according to our data. Variant chr5-156594940-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8177.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	NM_000337.6	c.391G>C	p.Ala131Pro	missense_variant	Exon 6 of 9	ENST00000337851.9	NP_000328.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000337851.9	c.391G>C	p.Ala131Pro	missense_variant	Exon 6 of 9	1	NM_000337.6	ENSP00000338343.4
SGCD	ENST00000435422.7	c.388G>C	p.Ala130Pro	missense_variant	Exon 5 of 8	1		ENSP00000403003.2
SGCD	ENST00000517913.5	c.391G>C	p.Ala131Pro	missense_variant	Exon 8 of 10	5		ENSP00000429378.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D;.
Eigen	Benign	0.027
Eigen_PC	Benign	0.034
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.4	.;L;.
PhyloP100		4.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.99	D;P;P
Vest4		0.91
MutPred		0.80		.;Loss of helix (P = 0.0123);.;
MVP		0.95
MPC		0.30
ClinPred		0.76	D
GERP RS		3.9
Varity_R		0.36
gMVP		0.81
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs267607045; hg19: chr5-156021950;