Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005660.3(SLC35A2):c.818G>A(p.Gly273Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G273A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

SLC35A2
NM_005660.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Publications

1 publications found

Variant links:

Genes affected

SLC35A2 (HGNC:11022): (solute carrier family 35 member A2) This gene encodes a member of the nucleotide-sugar transporter family. The encoded protein is a multi-pass membrane protein. It transports UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. Mutations in this gene cause congenital disorder of glycosylation type IIm (CDG2M). Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

SLC35A2 Gene-Disease associations (from GenCC):

SLC35A2-congenital disorder of glycosylation
Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

SLC35A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005660.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC35A2	NM_005660.3	MANE Select	c.818G>A	p.Gly273Asp	missense	Exon 4 of 5	NP_005651.1
SLC35A2	NM_001282651.2		c.902G>A	p.Gly301Asp	missense	Exon 5 of 5	NP_001269580.1
SLC35A2	NM_001282650.2		c.857G>A	p.Gly286Asp	missense	Exon 4 of 4	NP_001269579.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC35A2	ENST00000247138.11	TSL:1 MANE Select	c.818G>A	p.Gly273Asp	missense	Exon 4 of 5	ENSP00000247138.5
SLC35A2	ENST00000376521.6	TSL:1	c.818G>A	p.Gly273Asp	missense	Exon 4 of 4	ENSP00000365704.1
SLC35A2	ENST00000445167.7	TSL:1	c.427-199G>A		intron	N/A	ENSP00000402726.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.74

REVEL

Uncertain

0.38

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.82

Vest4

0.86

MutPred

0.74

Loss of catalytic residue at V274 (P = 0.0712)

MVP

0.61

MPC

1.4

ClinPred

0.82

GERP RS

5.0

Varity_R

0.46

gMVP

0.98

Mutation Taster

=1/99

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-48905091-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over