rs144743676

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP3BP4_ModerateBS1_Supporting

The ENST00000381431.10(SGCB):​c.151C>T​(p.Arg51Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00034 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

SGCB
ENST00000381431.10 missense

Scores

6
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.40
Variant links:
Genes affected
SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.09285295).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000302 (46/152208) while in subpopulation AMR AF= 0.0015 (23/15308). AF 95% confidence interval is 0.00103. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SGCBNM_000232.5 linkuse as main transcriptc.151C>T p.Arg51Cys missense_variant 2/6 ENST00000381431.10 NP_000223.1
SGCBXM_047416074.1 linkuse as main transcriptc.34-3660C>T intron_variant XP_047272030.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SGCBENST00000381431.10 linkuse as main transcriptc.151C>T p.Arg51Cys missense_variant 2/61 NM_000232.5 ENSP00000370839 P1Q16585-1
SGCBENST00000506357.5 linkuse as main transcriptc.139C>T p.Arg47Cys missense_variant, NMD_transcript_variant 2/55 ENSP00000421235
SGCBENST00000514133.1 linkuse as main transcriptc.118C>T p.Arg40Cys missense_variant, NMD_transcript_variant 1/45 ENSP00000425818

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00150
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000171
AC:
43
AN:
251468
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000344
AC:
502
AN:
1461344
Hom.:
0
Cov.:
31
AF XY:
0.000358
AC XY:
260
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000395
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000318
Hom.:
0
Bravo
AF:
0.000366
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 02, 2023- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Dec 31, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2022This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 51 of the SGCB protein (p.Arg51Cys). This variant is present in population databases (rs144743676, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 92659). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 11, 2021- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 11, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2018- -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.48
T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.97
D
MetaRNN
Benign
0.093
T
MetaSVM
Uncertain
0.30
D
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-2.7
D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.90
MVP
0.91
MPC
0.37
ClinPred
0.78
D
GERP RS
4.4
Varity_R
0.30
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

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

Other links and lift over

dbSNP: rs144743676; hg19: chr4-52899689; COSMIC: COSV67341370; API