dbSNP rs762114570: SGCB:p.Asn199PhefsTer17 (chr4-52028752-ACATT-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000232.5(SGCB):c.595_598delAATG(p.Asn199PhefsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

SGCB
NM_000232.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.84

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-52028752-ACATT-A is Pathogenic according to our data. Variant chr4-52028752-ACATT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52028752-ACATT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.595_598delAATG	p.Asn199PhefsTer17	frameshift_variant	Exon 4 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	XM_047416074.1 link	c.385_388delAATG	p.Asn129PhefsTer17	frameshift_variant	Exon 3 of 5		XP_047272030.1
SGCB	XM_047416075.1 link	c.298_301delAATG	p.Asn100PhefsTer17	frameshift_variant	Exon 3 of 5		XP_047272031.1
SGCB	XM_047416076.1 link	c.298_301delAATG	p.Asn100PhefsTer17	frameshift_variant	Exon 3 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SGCB	ENST00000381431.10 link	c.595_598delAATG	p.Asn199PhefsTer17	frameshift_variant	Exon 4 of 6	1	NM_000232.5	ENSP00000370839.6	Q16585-1
SGCB	ENST00000506357.5 link	n.377_380delAATG		downstream_gene_variant		5		ENSP00000421235.1	H0Y8J3
SGCB	ENST00000514133.1 link	n.390_393delAATG		downstream_gene_variant		5		ENSP00000425818.1	H0YA15

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251424

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E

Pathogenic:3

Dec 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 12566530). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556837). This variant is present in population databases (rs762114570, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Asn199Phefs*17) 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over