rs886044103

Variant names:

• chr4-52038245-C-CGCCGCT
• rs886044103
• NM_000232.5:c.9_14dupAGCGGC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP3 BS1

The NM_000232.5(SGCB):​c.9_14dupAGCGGC​(p.Ala4_Ala5dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,292,950 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. A5A) has been classified as Likely benign. The gene SGCB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SGCB NM_000232.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.763
• Publications: 1 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: Likely_benign. The variant received -3 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, 12 uncertain in NM_000232.5
• BP3: Nonframeshift variant in repetitive region in NM_000232.5
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00035 (53/151516) while in subpopulation AMR AF = 0.00335 (51/15208). AF 95% confidence interval is 0.00262. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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_14dupAGCGGC	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.9_14dupAGCGGC	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-399_-394dupAGCGGC		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_14dupAGCGGC	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.9_14dupAGCGGC	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.9_14dupAGCGGC	p.Ala4_Ala5dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.000350 AC: 53 AN: 151408 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00336

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 42596 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000394 AC: 45 AN: 1141434 Hom.: 0 Cov.: 31 AF XY: 0.0000453 AC XY: 25 AN XY: 551522

African (AFR) AF: 0.00 AC: 0 AN: 23900

American (AMR) AF: 0.000895 AC: 16 AN: 17880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17346

East Asian (EAS) AF: 0.00 AC: 0 AN: 25160

South Asian (SAS) AF: 0.0000281 AC: 1 AN: 35620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3118

European-Non Finnish (NFE) AF: 0.0000158 AC: 15 AN: 948984

Other (OTH) AF: 0.000286 AC: 13 AN: 45474

GnomAD4 genome AF: 0.000350 AC: 53 AN: 151516 Hom.: 0 Cov.: 32 AF XY: 0.000473 AC XY: 35 AN XY: 74044

African (AFR) AF: 0.0000241 AC: 1 AN: 41486

American (AMR) AF: 0.00335 AC: 51 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67756

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs886044103; hg19: chr4-52904411;