Genetic Variant NM_000232.5:c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG (chr4-52038237-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PS1_Moderate

The NM_000232.5(SGCB):c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG(p.Ala2fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,114,206 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

SGCB
NM_000232.5 frameshift, start_lost

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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 104 pathogenic variants in the truncated region.

PS1

Another start lost variant in NM_000232.5 (SGCB) was described as [Pathogenic] in ClinVar

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala2fs	frameshift_variant, start_lost	Exon 1 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	NM_000232.5 link	c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala2fs	frameshift_variant, start_lost	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1
SGCB	ENST00000381431.10 link	c.-10_22delGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000628

AC:

AN:

1114206

Hom.:

AF XY:

0.00000373

AC XY:

AN XY:

536468

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23210

American (AMR)

AF:

0.00

AC:

AN:

16084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16098

East Asian (EAS)

AF:

0.00

AC:

AN:

24044

South Asian (SAS)

AF:

0.0000307

AC:

AN:

32582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3016

European-Non Finnish (NFE)

AF:

0.00000643

AC:

AN:

932432

Other (OTH)

AF:

0.00

AC:

AN:

44060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00406385), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over