4-52028925-CAA-CAAA

Variant names:

• chr4-52028925-C-CA
• rs762831481
• NM_000232.5:c.430-5dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000232.5(SGCB):​c.430-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000643 in 1,601,472 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: SGCB NM_000232.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.54
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 4-52028925-C-CA is Benign according to our data. Variant chr4-52028925-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285749.

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.430-5dupT		splice_region intron	N/A	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.220-5dupT		splice_region intron	N/A	NP_001427448.1
	SGCB	NM_001440520.1		c.133-5dupT		splice_region intron	N/A	NP_001427449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.430-5_430-4insT		splice_region intron	N/A	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.430-17_430-16insT		intron	N/A	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.430-5_430-4insT		splice_region intron	N/A	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151396 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.0000295

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000486 AC: 12 AN: 247150 AF XY: 0.0000524

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000676 AC: 98 AN: 1450076 Hom.: 0 Cov.: 29 AF XY: 0.0000554 AC XY: 40 AN XY: 722086

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

African (AFR) AF: 0.000181 AC: 6 AN: 33122

American (AMR) AF: 0.000158 AC: 7 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39596

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85666

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000662 AC: 73 AN: 1102506

Other (OTH) AF: 0.0000834 AC: 5 AN: 59972

⚠️ 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 AF: 0.0000330 AC: 5 AN: 151396 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73916

African (AFR) AF: 0.0000243 AC: 1 AN: 41182

American (AMR) AF: 0.0000659 AC: 1 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67858

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.0000549

EpiControl AF: 0.0000597

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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: rs762831481; hg19: chr4-52895091; COSMIC: COSV67341009;