4-52038237-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGCCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000232.5(SGCB):c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG(p.Ala8GlyfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,265,076 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

SGCB
NM_000232.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.09

Publications

1 publications found

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]

SGCB Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2E
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

SGCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 89 pathogenic variants in the truncated region.

PP5

Variant 4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC is Pathogenic according to our data. Variant chr4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466601.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer22	frameshift_variant	Exon 1 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	NM_001440519.1 link	c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer16	frameshift_variant	Exon 1 of 5		NP_001427448.1
SGCB	NM_001440520.1 link	c.-417_-386dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 7		NP_001427449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer22	frameshift_variant	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1
SGCB	ENST00000506357.5 link	n.-25_7dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000421235.1		H0Y8J3

Frequencies

GnomAD3 genomes

AF:

0.0000597

AC:

AN:

150846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000969

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:

0.0000741

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000790

AC:

AN:

1114230

Hom.:

Cov.:

AF XY:

0.0000764

AC XY:

AN XY:

536482

show subpopulations

African (AFR)

AF:

0.0000862

AC:

AN:

23212

American (AMR)

AF:

0.00

AC:

AN:

16088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16098

East Asian (EAS)

AF:

0.00

AC:

AN:

24044

South Asian (SAS)

AF:

0.00

AC:

AN:

32586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3016

European-Non Finnish (NFE)

AF:

0.0000922

AC:

AN:

932444

Other (OTH)

AF:

0.00

AC:

AN:

44062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000597

AC:

AN:

150846

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73642

show subpopulations

African (AFR)

AF:

0.0000969

AC:

AN:

41276

American (AMR)

AF:

0.00

AC:

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000741

AC:

AN:

67468

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E

Pathogenic:4

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the SGCB gene. It may leave the encoded amino acid sequence of the SGCB protein unchanged or may create a premature translational stop signal (p.Ala8Glyfs*22). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 12746421, 25862795; internal data). This variant is also known as c.-10_22dup (Non-coding), ‚Äì22+10dup, and PTC+25aa. ClinVar contains an entry for this variant (Variation ID: 466601). Studies have shown that this variant alters SGCB gene expression (PMID: 25862795). For these reasons, this variant has been classified as Pathogenic. -

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 04, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Oct 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SGCB c.-10_22dup32 is located in the untranslated mRNA region upstream and the coding region including the initiation codon.The variant was absent in 37246 control chromosomes (gnomAD v2), however, it is found in 9/150846 controls in gnomAD v3. c.-10_22dup32 has been reported in the literature in multiple individuals affected with mild Limb-Girdle Muscular Dystrophy in homozygous state (Boito_2003, Semplicini_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is predicted to result in p.Ala8Glyfs*22 if the first initiation codon is utilized for translation. However, biochemical data of residual sarcoglycan expression in skeletal muscle and mild phenotype in variant carriers suggest that the second initiation codon in the mutant gene may also be utilized, which results in a normal protein (Semplicini_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Although this variant has been found in mutliple patients, due to lack of functional evidence, the variant was classified as likely pathogenic. -

not provided

Uncertain:1

Aug 21, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=26/174

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over