4-52038236-AGCCGCCGCC-AGCCGCCGCCGCCGCC

Variant names:

• chr4-52038236-A-AGCCGCC
• rs768838951
• NM_000232.5:c.18_23dupGGCGGC

Variant summary

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

The NM_000232.5(SGCB):​c.18_23dupGGCGGC​(p.Ala7_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 0.000172 in 1,286,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: SGCB NM_000232.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-390_-385dupGGCGGC		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.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.0000465 AC: 7 AN: 150690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000593

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 214 AN: 1135462 Hom.: 0 Cov.: 31 AF XY: 0.000192 AC XY: 105 AN XY: 548176

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

American (AMR) AF: 0.000170 AC: 3 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: 0.0000286 AC: 1 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: 0.000219 AC: 207 AN: 945430

Other (OTH) AF: 0.0000664 AC: 3 AN: 45152

GnomAD4 genome AF: 0.0000465 AC: 7 AN: 150690 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73560

African (AFR) AF: 0.0000243 AC: 1 AN: 41180

American (AMR) AF: 0.0000661 AC: 1 AN: 15128

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

East Asian (EAS) AF: 0.000196 AC: 1 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: 0.0000593 AC: 4 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, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (2)
-	2	-	not provided (2)

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: rs768838951; hg19: chr4-52904402;