4-52021050-A-G

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.*2907T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 152,302 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: SGCB NM_000232.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.645

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 (BayesDel_noAF=-0.83).
• BP6: Variant 4-52021050-A-G is Benign according to our data. Variant chr4-52021050-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348851.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00487 (742/152302) while in subpopulation NFE AF= 0.00744 (506/68018). AF 95% confidence interval is 0.0069. There are 4 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCB	NM_000232.5	c.*2907T>C		3_prime_UTR_variant	6/6	ENST00000381431.10
SGCB	XM_047416074.1	c.*2907T>C		3_prime_UTR_variant	5/5
SGCB	XM_047416075.1	c.*2907T>C		3_prime_UTR_variant	5/5
SGCB	XM_047416076.1	c.*2907T>C		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCB	ENST00000381431.10	c.*2907T>C		3_prime_UTR_variant	6/6	1	NM_000232.5	P1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 744 AN: 152184 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00487 AC: 742 AN: 152302 Hom.: 4 Cov.: 32 AF XY: 0.00451 AC XY: 336 AN XY: 74468

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00744

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00542 Hom.: 0

Bravo AF: 0.00556

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Qualitative or quantitative defects of beta-sarcoglycan Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

SGCB: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.8
Dann	Benign	0.66

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: rs138349341; hg19: chr4-52887216;