rs1553940660

Variant names:

• chr4-52033424-TACTC-T
• rs1553940660
• NM_000232.5:c.243+3_243+6delGAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000232.5(SGCB):​c.243+3_243+6delGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SGCB NM_000232.5 splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.84
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-52033424-TACTC-T is Pathogenic according to our data. Variant chr4-52033424-TACTC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 554840.Status of the report is criteria_provided_single_submitter, 1 stars.

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.243+3_243+6delGAGT		splice_region intron	N/A	NP_000223.1
	SGCB	NM_001440519.1		c.34-3565_34-3562delGAGT		intron	N/A	NP_001427448.1
	SGCB	NM_001440520.1		c.-165+3_-165+6delGAGT		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.243+3_243+6delGAGT		splice_region intron	N/A	ENSP00000370839.6
	SGCB	ENST00000899666.1		c.243+3_243+6delGAGT		splice_region intron	N/A	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.243+3_243+6delGAGT		splice_region intron	N/A	ENSP00000582525.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425326 Hom.: 0 AF XY: 0.00000281 AC XY: 2 AN XY: 711598

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078736

Other (OTH) AF: 0.00 AC: 0 AN: 59252

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -3
DS_DL_spliceai		0.98		Position offset: 7

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

Other links and lift over

dbSNP: rs1553940660; hg19: chr4-52899590;