chr5-156508602-A-G

Variant names:

• chr5-156508602-A-G
• rs769883857
• NM_000337.6:c.194A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000337.6(SGCD):​c.194A>G​(p.Asp65Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000208 in 1,440,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D65D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SGCD NM_000337.6 missense, splice_region
• Scores: Splicing: ADA: 0.8853
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000337.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	NM_000337.6	MANE Select	c.194A>G	p.Asp65Gly	missense splice_region	Exon 4 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.191A>G	p.Asp64Gly	missense splice_region	Exon 3 of 8	NP_001121681.1
	SGCD	NM_172244.3		c.194A>G	p.Asp65Gly	missense splice_region	Exon 4 of 8	NP_758447.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	ENST00000337851.9	TSL:1 MANE Select	c.194A>G	p.Asp65Gly	missense splice_region	Exon 4 of 9	ENSP00000338343.4
	SGCD	ENST00000435422.7	TSL:1	c.191A>G	p.Asp64Gly	missense splice_region	Exon 3 of 8	ENSP00000403003.2
	SGCD	ENST00000517913.5	TSL:5	c.194A>G	p.Asp65Gly	missense splice_region	Exon 6 of 10	ENSP00000429378.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247462 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440428 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718032

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33050

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093018

Other (OTH) AF: 0.00 AC: 0 AN: 59636

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000828 AC: 1

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

May 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 65 of the SGCD protein (p.Asp65Gly). This variant is present in population databases (rs769883857, gnomAD 0.01%). 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: 566569). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.84
Sift	Benign	0.070	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.53		Gain of helix (P = 0.132)
MVP		1.0
MPC		0.63
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.43
gMVP		0.76
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.67
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: rs769883857; hg19: chr5-155935612;