rs115928999

chr4-52033582-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000232.5(SGCB):c.92G>T(p.Ser31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,613,948 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.805

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008035511).
• BP6: Variant 4-52033582-C-A is Benign according to our data. Variant chr4-52033582-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92662.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr4-52033582-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00242 (369/152288) while in subpopulation AFR AF= 0.0084 (349/41536). AF 95% confidence interval is 0.00768. There are 2 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCB	NM_000232.5	c.92G>T	p.Ser31Ile	missense_variant	2/6	ENST00000381431.10
SGCB	XM_047416074.1	c.34-3719G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCB	ENST00000381431.10	c.92G>T	p.Ser31Ile	missense_variant	2/6	1	NM_000232.5	P1
SGCB	ENST00000506357.5	c.80G>T	p.Ser27Ile	missense_variant, NMD_transcript_variant	2/5	5
SGCB	ENST00000514133.1	c.59G>T	p.Ser20Ile	missense_variant, NMD_transcript_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00838

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000497 AC: 125 AN: 251468 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135910

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.000289

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727140

Gnomad4 AFR exome AF: 0.00806

Gnomad4 AMR exome AF: 0.000470

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: 0.00000540

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74476

Gnomad4 AFR AF: 0.00840

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.00249

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.92G>T (p.S31I) alteration is located in exon 2 (coding exon 2) of the SGCB gene. This alteration results from a G to T substitution at nucleotide position 92, causing the serine (S) at amino acid position 31 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 12, 2020

- -

Autosomal recessive limb-girdle muscular dystrophy type 2E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.0060	B
Vest4		0.22
MVP		0.68
MPC		0.089
ClinPred		0.0079	T
GERP RS		4.1
Varity_R		0.058
gMVP		0.57

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

Other links and lift over

dbSNP: rs115928999; hg19: chr4-52899748;