rs753240054

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000337.6(SGCD):​c.832G>A​(p.Ala278Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,612,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SGCD
NM_000337.6 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.554
Variant links:
Genes affected
SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0112119615).
BP6
Variant 5-156759349-G-A is Benign according to our data. Variant chr5-156759349-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464023.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr5-156759349-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000526 (8/152174) while in subpopulation EAS AF= 0.00154 (8/5192). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SGCDNM_000337.6 linkc.832G>A p.Ala278Thr missense_variant Exon 9 of 9 ENST00000337851.9 NP_000328.2 Q92629-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SGCDENST00000337851.9 linkc.832G>A p.Ala278Thr missense_variant Exon 9 of 9 1 NM_000337.6 ENSP00000338343.4 Q92629-2
SGCDENST00000435422.7 linkc.829G>A p.Ala277Thr missense_variant Exon 8 of 8 1 ENSP00000403003.2 Q92629-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00154
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000157
AC:
39
AN:
248436
Hom.:
0
AF XY:
0.000148
AC XY:
20
AN XY:
134762
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00211
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000384
AC:
56
AN:
1460024
Hom.:
0
Cov.:
30
AF XY:
0.0000358
AC XY:
26
AN XY:
726180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00131
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00154
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ExAC
AF:
0.0000993
AC:
12

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Qualitative or quantitative defects of delta-sarcoglycan Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 provided Uncertain:1
Jan 03, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2F Benign:1
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
9.2
DANN
Benign
0.70
DEOGEN2
Uncertain
0.48
T;.
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.063
N
LIST_S2
Benign
0.35
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
-0.32
N;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.24
N;N
REVEL
Benign
0.20
Sift
Benign
0.61
T;T
Sift4G
Benign
0.74
T;T
Polyphen
0.0
B;B
Vest4
0.041
MutPred
0.31
Gain of sheet (P = 0.1945);.;
MVP
0.32
MPC
0.12
ClinPred
0.020
T
GERP RS
2.5
Varity_R
0.030
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs753240054; hg19: chr5-156186360; API