rs781364428

Variant names:

• chr4-52038236-A-AGCCGCCGCCGCCGCT
• rs781364428
• NM_000232.5:c.9_23dupAGCGGCGGCGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP3

The NM_000232.5(SGCB):​c.9_23dupAGCGGCGGCGGCGGC​(p.Ala4_Ala8dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,690 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign. The gene SGCB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCB NM_000232.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.16
• 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, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Specifications for SGCB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000232.5
• BP3: Nonframeshift variant in repetitive region in NM_000232.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.9_23dupAGCGGCGGCGGCGGC	p.Ala4_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.9_23dupAGCGGCGGCGGCGGC	p.Ala4_Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-399_-385dupAGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 7	NP_001427449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.9_23dupAGCGGCGGCGGCGGC	p.Ala4_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.9_23dupAGCGGCGGCGGCGGC	p.Ala4_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.9_23dupAGCGGCGGCGGCGGC	p.Ala4_Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000440 AC: 5 AN: 1135466 Hom.: 0 Cov.: 31 AF XY: 0.00000547 AC XY: 3 AN XY: 548178

African (AFR) AF: 0.00 AC: 0 AN: 23738

American (AMR) AF: 0.00 AC: 0 AN: 17650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16976

East Asian (EAS) AF: 0.00 AC: 0 AN: 24822

South Asian (SAS) AF: 0.00 AC: 0 AN: 34980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3090

European-Non Finnish (NFE) AF: 0.00000529 AC: 5 AN: 945434

Other (OTH) AF: 0.00 AC: 0 AN: 45152

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150690 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73560

African (AFR) AF: 0.00 AC: 0 AN: 41180

American (AMR) AF: 0.00 AC: 0 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67486

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	3	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs781364428; hg19: chr4-52904402;