4-52038236-AGCCGCCGCC-AGCCGCCGCCGCC

Variant names:

• chr4-52038236-A-AGCC
• rs768838951
• NM_000232.5:c.21_23dupGGC

Variant summary

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

The NM_000232.5(SGCB):​c.21_23dupGGC​(p.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 0.000376 in 1,286,260 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.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SGCB NM_000232.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• 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

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.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-387_-385dupGGC		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.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.000465 AC: 70 AN: 150688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000934

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 8 AN: 37246 AF XY: 0.000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000242

Gnomad ASJ exome AF: 0.000584

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000364 AC: 413 AN: 1135466 Hom.: 0 Cov.: 31 AF XY: 0.000394 AC XY: 216 AN XY: 548178

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

American (AMR) AF: 0.000227 AC: 4 AN: 17650

Ashkenazi Jewish (ASJ) AF: 0.000825 AC: 14 AN: 16976

East Asian (EAS) AF: 0.0000403 AC: 1 AN: 24822

South Asian (SAS) AF: 0.0000572 AC: 2 AN: 34980

European-Finnish (FIN) AF: 0.0000847 AC: 2 AN: 23624

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

European-Non Finnish (NFE) AF: 0.000396 AC: 374 AN: 945434

Other (OTH) AF: 0.000354 AC: 16 AN: 45152

GnomAD4 genome AF: 0.000471 AC: 71 AN: 150794 Hom.: 0 Cov.: 32 AF XY: 0.000448 AC XY: 33 AN XY: 73678

African (AFR) AF: 0.000121 AC: 5 AN: 41298

American (AMR) AF: 0.0000660 AC: 1 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000934 AC: 63 AN: 67474

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000336

Asia WGS AF: 0.000300 AC: 1 AN: 3340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (3)
-	3	-	not provided (3)
-	1	-	not specified (1)

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;