14-96385562-C-G

Variant names:

• chr14-96385562-C-G
• NM_016472.5:c.298C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016472.5(GSKIP):​c.298C>G​(p.Gln100Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GSKIP NM_016472.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107233435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSKIP	NM_016472.5	c.298C>G	p.Gln100Glu	missense_variant	Exon 4 of 4	ENST00000555181.6	NP_057556.2
GSKIP	NM_001271904.1	c.298C>G	p.Gln100Glu	missense_variant	Exon 4 of 4		NP_001258833.1
GSKIP	NM_001271905.2	c.298C>G	p.Gln100Glu	missense_variant	Exon 4 of 4		NP_001258834.1
GSKIP	NM_001271906.2	c.298C>G	p.Gln100Glu	missense_variant	Exon 3 of 3		NP_001258835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSKIP	ENST00000555181.6	c.298C>G	p.Gln100Glu	missense_variant	Exon 4 of 4	1	NM_016472.5	ENSP00000450420.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460124 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.298C>G (p.Q100E) alteration is located in exon 3 (coding exon 2) of the GSKIP gene. This alteration results from a C to G substitution at nucleotide position 298, causing the glutamine (Q) at amino acid position 100 to be replaced by a glutamic acid (E). 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	0.067
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.021	T;T;T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;.;.;.;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;L;L;L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.020	N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0070	B;B;B;B;.
Vest4		0.18
MutPred		0.38		Gain of catalytic residue at H104 (P = 0.0146);Gain of catalytic residue at H104 (P = 0.0146);Gain of catalytic residue at H104 (P = 0.0146);Gain of catalytic residue at H104 (P = 0.0146);Gain of catalytic residue at H104 (P = 0.0146);
MVP		0.12
MPC		0.44
ClinPred		0.36	T
GERP RS		5.5
Varity_R		0.097
gMVP		0.21

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: chr14-96851899;