chr17-50169151-C-T

Position:

• chr17-50169151-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000262018.8(SGCA):​c.644C>T​(p.Ser215Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SGCA ENST00000262018.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000262018.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 17-50169151-C-T is Pathogenic according to our data. Variant chr17-50169151-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551091.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr17-50169151-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.644C>T	p.Ser215Phe	missense_variant	6/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.584+579C>T		intron_variant			NP_001129169.1
SGCA	NR_135553.2	n.680C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.644C>T	p.Ser215Phe	missense_variant	6/10	1	NM_000023.4	ENSP00000262018	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function. ClinVar contains an entry for this variant (Variation ID: 551091). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 18285821). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 215 of the SGCA protein (p.Ser215Phe). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Sep 13, 2024	The SGCA variant c.644C>T was present in the homozygous state in 2 individuals in a 4-generation, consanguineous family. The variant is not present in population databases (gnomAD no frequency). REVEL score is 0.699. The variant has been detected in trans with a pathogenic variant PMID:18285821. The following ACMG criteria were applied in classifying this variant: PM2, PM3, PP3, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.75
MutPred		0.83		Loss of disorder (P = 0.0063);
MVP		1.0
MPC		0.44
ClinPred		0.86	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs750844090; hg19: chr17-48246512;