rs1553342786

Positions:

• chr1-235454243-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152490.5(B3GALNT2):​c.1223del​(p.Pro408LeufsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: B3GALNT2 NM_152490.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.54

Genes affected

B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-235454243-AG-A is Pathogenic according to our data. Variant chr1-235454243-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 540913.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B3GALNT2	NM_152490.5	c.1223del	p.Pro408LeufsTer10	frameshift_variant	10/12	ENST00000366600.8
B3GALNT2	XM_006711749.4	c.1223del	p.Pro408LeufsTer10	frameshift_variant	10/13
B3GALNT2	XM_017000394.2	c.1346del	p.Pro449LeufsTer10	frameshift_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B3GALNT2	ENST00000366600.8	c.1223del	p.Pro408LeufsTer10	frameshift_variant	10/12	1	NM_152490.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in B3GALNT2 are known to be pathogenic (PMID: 23453667). This variant has not been reported in the literature in individuals with B3GALNT2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro408Leufs*10) in the B3GALNT2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553342786; hg19: chr1-235617555;