X-48904529-TCACCCTACCAGGAAGGGTTCACGTGACACCCAGCTCTAGTCCCACACCCCTCCAGAAGTCTCAGTGACCTGGGAGAAAAGACCATCTCCCAAACCCAGAGGAGCCAGGCCCCGGAGGGTGGCGACTTGGGTCCTGCAGATGCCCAACACCCTCCACCCCAGTCCCCCTCCCTTGTGTCCCCCCATTGCTGCCAGCCCTCACTTCACCAGCACTGACTTTGGCAGAAAGGGCTCCGTGATGAGGTCTCCACGGTGGGAAGACAGCTGCGGTGGTGGTGGCTGCCC-CCTCCCG

Variant names:

• chrX-48904529-TCACCCTACCAGGAAGGGTTCACGTGACACCCAGCTCTAGTCCCACACCCCTCCAGAAGTCTCAGTGACCTGGGAGAAAAGACCATCTCCCAAACCCAGAGGAGCCAGGCCCCGGAGGGTGGCGACTTGGGTCCTGCAGATGCCCAACACCCTCCACCCCAGTCCCCCTCCCTTGTGTCCCCCCATTGCTGCCAGCCCTCACTTCACCAGCACTGACTTTGGCAGAAAGGGCTCCGTGATGAGGTCTCCACGGTGGGAAGACAGCTGCGGTGGTGGTGGCTGCCC-CCTCCCG
• ENST00000376521.6:c.1096_*198delGGGCAGCCACCACCACCGCAGCTGTCTTCCCACCGTGGAGACCTCATCACGGAGCCCTTTCTGCCAAAGTCAGTGCTGGTGAAGTGAGGGCTGGCAGCAATGGGGGGACACAAGGGAGGGGGACTGGGGTGGAGGGTGTTGGGCATCTGCAGGACCCAAGTCGCCACCCTCCGGGGCCTGGCTCCTCTGGGTTTGGGAGATGGTCTTTTCTCCCAGGTCACTGAGACTTCTGGAGGGGTGTGGGACTAGAGCTGGGTGTCACGTGAACCCTTCCTGGTAGGGTGAinsCGGGAGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_005660.3(SLC35A2):​c.1096_1163+217delGGGCAGCCACCACCACCGCAGCTGTCTTCCCACCGTGGAGACCTCATCACGGAGCCCTTTCTGCCAAAGTCAGTGCTGGTGAAGTGAGGGCTGGCAGCAATGGGGGGACACAAGGGAGGGGGACTGGGGTGGAGGGTGTTGGGCATCTGCAGGACCCAAGTCGCCACCCTCCGGGGCCTGGCTCCTCTGGGTTTGGGAGATGGTCTTTTCTCCCAGGTCACTGAGACTTCTGGAGGGGTGTGGGACTAGAGCTGGGTGTCACGTGAACCCTTCCTGGTAGGGTGAinsCGGGAGG​(p.Gly366fs) variant causes a frameshift, splice donor, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLC35A2 NM_005660.3 frameshift, splice_donor, splice_region, synonymous, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A2	NM_005660.3	c.1096_1163+217delGGGCAGCCACCACCACCGCAGCTGTCTTCCCACCGTGGAGACCTCATCACGGAGCCCTTTCTGCCAAAGTCAGTGCTGGTGAAGTGAGGGCTGGCAGCAATGGGGGGACACAAGGGAGGGGGACTGGGGTGGAGGGTGTTGGGCATCTGCAGGACCCAAGTCGCCACCCTCCGGGGCCTGGCTCCTCTGGGTTTGGGAGATGGTCTTTTCTCCCAGGTCACTGAGACTTCTGGAGGGGTGTGGGACTAGAGCTGGGTGTCACGTGAACCCTTCCTGGTAGGGTGAinsCGGGAGG	p.Gly366fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 4 of 5	ENST00000247138.11	NP_005651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11	c.1096_1163+217delGGGCAGCCACCACCACCGCAGCTGTCTTCCCACCGTGGAGACCTCATCACGGAGCCCTTTCTGCCAAAGTCAGTGCTGGTGAAGTGAGGGCTGGCAGCAATGGGGGGACACAAGGGAGGGGGACTGGGGTGGAGGGTGTTGGGCATCTGCAGGACCCAAGTCGCCACCCTCCGGGGCCTGGCTCCTCTGGGTTTGGGAGATGGTCTTTTCTCCCAGGTCACTGAGACTTCTGGAGGGGTGTGGGACTAGAGCTGGGTGTCACGTGAACCCTTCCTGGTAGGGTGAinsCGGGAGG	p.Gly366fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 4 of 5	1	NM_005660.3	ENSP00000247138.5

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 28 amino acid(s) are replaced with 10 different amino acid(s); Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

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

Other links and lift over

hg19: chrX-48761806;