14-96382281-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016472.5(GSKIP):c.34A>G(p.Ser12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,612,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GSKIP
NM_016472.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.88

Variant links:

Genes affected

GSKIP (HGNC:20343): (GSK3B interacting protein) This gene encodes a protein that is involved as a negative regulator of GSK3-beta in the Wnt signaling pathway. The encoded protein may play a role in the retinoic acid signaling pathway by regulating the functional interactions between GSK3-beta, beta-catenin and cyclin D1, and it regulates the beta-catenin/N-cadherin pool. The encoded protein contains a GSK3-beta interacting domain (GID) in its C-terminus, which is similar to the GID of Axin. The protein also contains an evolutionarily conserved RII-binding domain, which facilitates binding with protein kinase-A and GSK3-beta, enabling its role as an A-kinase anchoring protein. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2012]

GSKIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021021158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSKIP	NM_016472.5 link	c.34A>G	p.Ser12Gly	missense_variant	Exon 3 of 4	ENST00000555181.6	NP_057556.2	Q9P0R6A0A024R6P6
GSKIP	NM_001271904.1 link	c.34A>G	p.Ser12Gly	missense_variant	Exon 3 of 4		NP_001258833.1	Q9P0R6A0A024R6P6
GSKIP	NM_001271905.2 link	c.34A>G	p.Ser12Gly	missense_variant	Exon 3 of 4		NP_001258834.1	Q9P0R6A0A024R6P6
GSKIP	NM_001271906.2 link	c.34A>G	p.Ser12Gly	missense_variant	Exon 2 of 3		NP_001258835.1	Q9P0R6A0A024R6P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSKIP	ENST00000555181.6 link	c.34A>G	p.Ser12Gly	missense_variant	Exon 3 of 4	1	NM_016472.5	ENSP00000450420.1		Q9P0R6

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

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:

0.00

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251026

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460242

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000362

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:

0.00

Gnomad4 OTH

AF:

0.000476

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34A>G (p.S12G) alteration is located in exon 2 (coding exon 1) of the GSKIP gene. This alteration results from a A to G substitution at nucleotide position 34, causing the serine (S) at amino acid position 12 to be replaced by a glycine (G). 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

Benign

0.061

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.045

T;T;.;T;T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.59

T;.;T;.;.;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.021

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;.;N;N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.070

Sift

Benign

0.43

T;T;T;T;T;T

Sift4G

Benign

0.44

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;B;.

Vest4

0.068

MutPred

0.16

Loss of phosphorylation at S12 (P = 0.0072);Loss of phosphorylation at S12 (P = 0.0072);Loss of phosphorylation at S12 (P = 0.0072);Loss of phosphorylation at S12 (P = 0.0072);Loss of phosphorylation at S12 (P = 0.0072);Loss of phosphorylation at S12 (P = 0.0072);

MVP

0.10

MPC

0.37

ClinPred

0.014

GERP RS

2.2

Varity_R

0.045

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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