4-52038236-AGCCGCCGCC-AGCCGCC

Variant names:

• chr4-52038236-AGCC-A
• rs768838951
• NM_000232.5:c.21_23delGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP3 BP6

The NM_000232.5(SGCB):​c.21_23delGGC​(p.Ala8del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,131,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCB NM_000232.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 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: Uncertain_significance. The variant received 0 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, 13 uncertain in NM_000232.5
• BP3: Nonframeshift variant in repetitive region in NM_000232.5
• BP6: Variant 4-52038236-AGCC-A is Benign according to our data. Variant chr4-52038236-AGCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 978759.

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_23delGGC	p.Ala8del	disruptive_inframe_deletion	Exon 1 of 6	NP_000223.1
	SGCB	NM_001440519.1		c.21_23delGGC	p.Ala8del	disruptive_inframe_deletion	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-387_-385delGGC		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_23delGGC	p.Ala8del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000370839.6
	SGCB	ENST00000899666.1		c.21_23delGGC	p.Ala8del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.21_23delGGC	p.Ala8del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150682 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00408 AC: 152 AN: 37246 AF XY: 0.00427

Gnomad AFR exome AF: 0.00189

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00629

Gnomad FIN exome AF: 0.00449

Gnomad NFE exome AF: 0.00388

Gnomad OTH exome AF: 0.00436

GnomAD4 exome AF: 0.000435 AC: 492 AN: 1131814 Hom.: 0 AF XY: 0.000531 AC XY: 290 AN XY: 546038

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000423 AC: 10 AN: 23650

American (AMR) AF: 0.00289 AC: 50 AN: 17302

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 19 AN: 16808

East Asian (EAS) AF: 0.000202 AC: 5 AN: 24706

South Asian (SAS) AF: 0.00339 AC: 117 AN: 34470

European-Finnish (FIN) AF: 0.00123 AC: 29 AN: 23524

Middle Eastern (MID) AF: 0.000975 AC: 3 AN: 3078

European-Non Finnish (NFE) AF: 0.000249 AC: 235 AN: 943298

Other (OTH) AF: 0.000534 AC: 24 AN: 44978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150788 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73672

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.00 AC: 0 AN: 15144

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10226

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67476

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

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=78/22	polymorphism

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: rs768838951; hg19: chr4-52904402; COSMIC: COSV107497977; COSMIC: COSV107497977;