rs201131924

Positions:

• chr17-50169187-C-G
• chr17-50169187-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000023.4(SGCA):​c.680C>G​(p.Pro227Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 3.17

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 Uncertain_significance. Variant got 1 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, 7 uncertain in NM_000023.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10814431).
• BP6: Variant 17-50169187-C-G is Benign according to our data. Variant chr17-50169187-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198033.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.680C>G	p.Pro227Arg	missense_variant	6/10	ENST00000262018.8
SGCA	NM_001135697.3	c.584+615C>G		intron_variant
SGCA	NR_135553.2	n.716C>G		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.680C>G	p.Pro227Arg	missense_variant	6/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000298 AC: 75 AN: 251360 Hom.: 1 AF XY: 0.000346 AC XY: 47 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.000204 AC XY: 148 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74424

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 17, 2019	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Sarcoglycanopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.50	N
REVEL	Uncertain	0.33
Sift	Benign	0.69	T
Sift4G	Benign	0.87	T
Polyphen		0.016	B
Vest4		0.30
MVP		0.99
MPC		0.36
ClinPred		0.039	T
GERP RS		4.1
Varity_R		0.081
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs201131924; hg19: chr17-48246548;