17-50168397-G-C

Variant names:

• chr17-50168397-G-C
• rs372210292
• NM_000023.4:c.409G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000023.4(SGCA):​c.409G>C​(p.Glu137Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000627 in 1,434,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E137G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 6.91
• Publications: 13 publications found

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000253730 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50168398-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9438.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-50168397-G-C is Pathogenic according to our data. Variant chr17-50168397-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554420.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000023.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.409G>C	p.Glu137Gln	missense	Exon 5 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.409G>C	p.Glu137Gln	missense	Exon 5 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.445G>C		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.409G>C	p.Glu137Gln	missense	Exon 5 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.409G>C	p.Glu137Gln	missense	Exon 5 of 8	ENSP00000345522.6	Q16586-2
	SGCA	ENST00000952408.1		c.499G>C	p.Glu167Gln	missense	Exon 5 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000627 AC: 9 AN: 1434424 Hom.: 0 Cov.: 33 AF XY: 0.00000563 AC XY: 4 AN XY: 710876

African (AFR) AF: 0.00 AC: 0 AN: 33106

American (AMR) AF: 0.00 AC: 0 AN: 40582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38586

South Asian (SAS) AF: 0.00 AC: 0 AN: 82090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098566

Other (OTH) AF: 0.0000843 AC: 5 AN: 59330

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2D (8)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.77
Sift	Benign	0.069	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.92		Loss of sheet (P = 0.0457)
MVP		0.98
MPC		1.1
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.20
gMVP		0.92
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372210292; hg19: chr17-48245758;