rs751466306

Positions:

chr17-50175406-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000023.4(SGCA):c.1133C>T(p.Ala378Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.58

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SGCA	NM_000023.4 linkuse as main transcript	c.1133C>T	p.Ala378Val	missense_variant	9/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3 linkuse as main transcript	c.761C>T	p.Ala254Val	missense_variant	7/8		NP_001129169.1
SGCA	NR_135553.2 linkuse as main transcript	n.960C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 linkuse as main transcript	c.1133C>T	p.Ala378Val	missense_variant	9/10	1	NM_000023.4	ENSP00000262018	P1	Q16586-1
	ENST00000504307.3 linkuse as main transcript	n.547-3229G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

247990

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460804

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 18, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 378 of the SGCA protein (p.Ala378Val). This variant is present in population databases (rs751466306, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SGCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 290288). 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. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.64

Sift

Benign

0.052

T;D

Sift4G

Uncertain

0.054

T;T

Polyphen

0.99

D;D

Vest4

0.42

MutPred

0.45

.;Loss of disorder (P = 0.1759);

MVP

0.99

MPC

1.1

ClinPred

0.84

GERP RS

4.6

Varity_R

0.19

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over