Genetic Variant IDNK:p.Ser13Arg (chr9-83623210-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_001001551.4(IDNK):c.39C>A(p.Ser13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,407,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

IDNK
NM_001001551.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36

Variant links:

Genes affected

IDNK (HGNC:31367): (IDNK gluconokinase) Predicted to enable gluconokinase activity. Predicted to be involved in D-gluconate catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

IDNK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, Cadd, FATHMM_MKL, M_CAP, MutationAssessor, PrimateAI, PROVEAN [when max_spliceai, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.39986566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDNK	NM_001001551.4 link	c.39C>A	p.Ser13Arg	missense_variant	Exon 1 of 5	ENST00000376419.5	NP_001001551.2	Q5T6J7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDNK	ENST00000376419.5 link	c.39C>A	p.Ser13Arg	missense_variant	Exon 1 of 5	1	NM_001001551.4	ENSP00000365601.4		Q5T6J7-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000637

AC:

AN:

1255166

Hom.:

Cov.:

AF XY:

0.00000327

AC XY:

AN XY:

611794

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:

0.00000393

Gnomad4 OTH exome

AF:

0.0000195

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.39C>A (p.S13R) alteration is located in exon 1 (coding exon 1) of the IDNK gene. This alteration results from a C to A substitution at nucleotide position 39, causing the serine (S) at amino acid position 13 to be replaced by an arginine (R). 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

0.97

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.42

T;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

4.2

.;.;H

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

1.0

.;.;D

Vest4

0.18

MutPred

0.57

Loss of glycosylation at S13 (P = 0.0043);Loss of glycosylation at S13 (P = 0.0043);Loss of glycosylation at S13 (P = 0.0043);

MVP

0.44

MPC

0.70

ClinPred

1.0

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.82

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over