NM_024089.3:c.1223A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024089.3(POGLUT2):​c.1223A>G​(p.Tyr408Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000028 ( 1 hom. )

Consequence

POGLUT2
NM_024089.3 missense

Scores

13
2
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02
Variant links:
Genes affected
POGLUT2 (HGNC:19350): (protein O-glucosyltransferase 2) This gene encodes a protein product localized to the lumen of the endoplasmic reticulum. As a member of the endoplasmic reticulum protein family the encoded protein contains a Lys-Asp-Glu-Leu or KDEL motif located at the extreme C-terminus which prevents all endoplasmic reticulum resident proteins from being secreted. Proteins carrying this motif are bound by a receptor in the Golgi apparatus so that the receptor-ligand complex returns to the endoplasmic reticulum. A processed non-transcribed pseudogene located in an intron of a sodium transporter gene on chromosome 5 has been defined for this gene. This gene has multiple transcript variants which are predicted to encode distinct isoforms. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.983

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POGLUT2NM_024089.3 linkc.1223A>G p.Tyr408Cys missense_variant Exon 7 of 10 ENST00000376004.5 NP_076994.2 Q6UW63
POGLUT2NM_001318732.2 linkc.566A>G p.Tyr189Cys missense_variant Exon 8 of 11 NP_001305661.1 Q6UW63
POGLUT2XM_005254075.4 linkc.1223A>G p.Tyr408Cys missense_variant Exon 7 of 9 XP_005254132.1
POGLUT2XM_047430604.1 linkc.566A>G p.Tyr189Cys missense_variant Exon 5 of 8 XP_047286560.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POGLUT2ENST00000376004.5 linkc.1223A>G p.Tyr408Cys missense_variant Exon 7 of 10 1 NM_024089.3 ENSP00000365172.4 Q6UW63

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000280
AC:
41
AN:
1461838
Hom.:
1
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000351
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1223A>G (p.Y408C) alteration is located in exon 7 (coding exon 7) of the KDELC1 gene. This alteration results from a A to G substitution at nucleotide position 1223, causing the tyrosine (Y) at amino acid position 408 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.079
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.12
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-8.1
D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.93
Loss of ubiquitination at K412 (P = 0.1564);
MVP
0.89
MPC
0.63
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.91
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-103441432; API