17-50175393-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000023.4(SGCA):c.1120C>T(p.Arg374Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,124 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (4 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.25

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040668547).
• BP6: Variant 17-50175393-C-T is Benign according to our data. Variant chr17-50175393-C-T is described in ClinVar as [Benign]. Clinvar id is 167678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50175393-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-50175393-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00523 (797/152392) while in subpopulation AFR AF= 0.0175 (727/41594). AF 95% confidence interval is 0.0164. There are 5 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.1120C>T	p.Arg374Cys	missense_variant	9/10	ENST00000262018.8
SGCA	NM_001135697.3	c.748C>T	p.Arg250Cys	missense_variant	7/8
SGCA	NR_135553.2	n.947C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.1120C>T	p.Arg374Cys	missense_variant	9/10	1	NM_000023.4	P1
	ENST00000504307.3	n.547-3216G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152274 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00171 AC: 424 AN: 248192 Hom.: 1 AF XY: 0.00131 AC XY: 177 AN XY: 134924

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000658 AC: 961 AN: 1460732 Hom.: 4 Cov.: 31 AF XY: 0.000590 AC XY: 429 AN XY: 726698

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00523 AC: 797 AN: 152392 Hom.: 5 Cov.: 33 AF XY: 0.00503 AC XY: 375 AN XY: 74516

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00198 Hom.: 3

Bravo AF: 0.00602

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00201 AC: 244

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 16, 2013

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 28, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2020

- -

Sarcoglycanopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.028	D;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0010	B;B
Vest4		0.21
MVP		0.90
MPC		0.48
ClinPred		0.0062	T
GERP RS		1.3
Varity_R		0.078
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35495899; hg19: chr17-48252754;