rs1553356208

Variant names:

• chr1-235504243-A-G
• rs1553356208
• NM_152490.5:c.10T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152490.5(B3GALNT2):​c.10T>C​(p.Trp4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000075 in 1,333,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: B3GALNT2 NM_152490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24
• Publications: 0 publications found

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]

B3GALNT2 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GALNT2	NM_152490.5	c.10T>C	p.Trp4Arg	missense_variant	Exon 1 of 12	ENST00000366600.8	NP_689703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B3GALNT2	ENST00000366600.8	c.10T>C	p.Trp4Arg	missense_variant	Exon 1 of 12	1	NM_152490.5	ENSP00000355559.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333858 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 657918

African (AFR) AF: 0.00 AC: 0 AN: 26806

American (AMR) AF: 0.00 AC: 0 AN: 30642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23312

East Asian (EAS) AF: 0.00 AC: 0 AN: 28856

South Asian (SAS) AF: 0.00 AC: 0 AN: 75566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32914

Middle Eastern (MID) AF: 0.000237 AC: 1 AN: 4228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056206

Other (OTH) AF: 0.00 AC: 0 AN: 55328

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 replaces tryptophan with arginine at codon 4 of the B3GALNT2 protein (p.Trp4Arg). The tryptophan residue is weakly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.44	N
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L;L
PhyloP100		4.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.25
Sift	Benign	0.047	D;.
Sift4G	Benign	0.069	T;D
Polyphen		0.93	P;D
Vest4		0.44
MutPred		0.73		Gain of methylation at W4 (P = 0.0139);Gain of methylation at W4 (P = 0.0139);
MVP		0.57
MPC		0.75
ClinPred		0.71	D
GERP RS		3.2
PromoterAI		-0.032	Neutral
Varity_R		0.42
gMVP		0.68
Mutation Taster		=84/16	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: rs1553356208; hg19: chr1-235667543;