chrX-48909843-C-A

Position:

• chrX-48909843-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005660.3(SLC35A2):​c.245G>T​(p.Cys82Phe) variant causes a missense change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant X-48909843-C-A is Pathogenic according to our data. Variant chrX-48909843-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453301.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-48909843-C-A is described in Lovd as [Pathogenic]. Variant chrX-48909843-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35A2	NM_005660.3	c.245G>T	p.Cys82Phe	missense_variant	2/5	ENST00000247138.11	NP_005651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11	c.245G>T	p.Cys82Phe	missense_variant	2/5	1	NM_005660.3	ENSP00000247138.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLC35A2-congenital disorder of glycosylation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jul 30, 2019

This individual has been reported in PMID: 30817854. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;D;.;.;T;D;D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.3	M;.;M;M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-8.4	D;D;D;D;D;.;D;D;.;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;.;D;D;D
Polyphen		1.0	D;.;D;D;.;D;.;.;.;D;.
Vest4		0.86
MutPred		0.75		Loss of catalytic residue at L83 (P = 0.0138);Loss of catalytic residue at L83 (P = 0.0138);Loss of catalytic residue at L83 (P = 0.0138);Loss of catalytic residue at L83 (P = 0.0138);.;.;.;.;Loss of catalytic residue at L83 (P = 0.0138);.;Loss of catalytic residue at L83 (P = 0.0138);
MVP		0.80
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557043622; hg19: chrX-48767120;