4-52038232-C-A

Variant names:

• chr4-52038232-C-A
• rs1448040082
• NM_000232.5:c.28G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000232.5(SGCB):​c.28G>T​(p.Glu10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 1,135,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: SGCB NM_000232.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.615
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 87 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-52038232-C-A is Pathogenic according to our data. Variant chr4-52038232-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 534947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.28G>T	p.Glu10*	stop_gained	Exon 1 of 6	ENST00000381431.10	NP_000223.1
SGCB	NM_001440519.1	c.28G>T	p.Glu10*	stop_gained	Exon 1 of 5		NP_001427448.1
SGCB	NM_001440520.1	c.-380G>T		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	c.28G>T	p.Glu10*	stop_gained	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6
SGCB	ENST00000506357.5	n.13G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000421235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000264 AC: 3 AN: 1135578 Hom.: 0 Cov.: 31 AF XY: 0.00000182 AC XY: 1 AN XY: 548368

African (AFR) AF: 0.0000421 AC: 1 AN: 23754

American (AMR) AF: 0.00 AC: 0 AN: 17662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16950

East Asian (EAS) AF: 0.00 AC: 0 AN: 24710

South Asian (SAS) AF: 0.00 AC: 0 AN: 35138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3098

European-Non Finnish (NFE) AF: 0.00000212 AC: 2 AN: 945512

Other (OTH) AF: 0.00 AC: 0 AN: 45104

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:2

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu10*) in the SGCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCB are known to be pathogenic (PMID: 15938573, 18285821). This variant is not present in population databases (gnomAD no frequency). 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: 534947). For these reasons, this variant has been classified as Pathogenic. -

Dec 17, 2024

Palindrome, Gene Kavoshgaran Aria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 12, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.27	N
PhyloP100		0.61
Vest4		0.36
GERP RS		2.9
PromoterAI		0.098	Neutral
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1448040082; hg19: chr4-52904398;