dbSNP rs749730618: CNKSR2:p.Gln63Lys (chrX-21426619-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014927.5(CNKSR2):c.187C>A(p.Gln63Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,205,231 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CNKSR2
NM_014927.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

CNKSR2 (HGNC:19701): (connector enhancer of kinase suppressor of Ras 2) This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

CNKSR2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNKSR2	NM_014927.5 link	c.187C>A	p.Gln63Lys	missense_variant	Exon 2 of 22	ENST00000379510.5	NP_055742.2	Q8WXI2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNKSR2	ENST00000379510.5 link	c.187C>A	p.Gln63Lys	missense_variant	Exon 2 of 22	1	NM_014927.5	ENSP00000368824.3		Q8WXI2-1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111647

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33819

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.00

GnomAD3 exomes

AF:

0.00000574

AC:

AN:

174183

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

59419

show subpopulations

Gnomad AFR exome

AF:

0.0000796

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:

9.14e-7

AC:

AN:

1093584

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359634

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111647

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33819

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;.;.;.;.;.;.;.;.;.;D;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.068

MutationAssessor

Pathogenic

3.3

M;.;M;.;M;.;.;.;.;.;M;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.4

.;.;D;.;D;D;.;.;.;.;D;.;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

.;.;D;.;D;D;.;.;.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;.;D;D;.;.;.;.;D;.;.

Polyphen

1.0

.;.;.;.;.;.;.;.;.;.;D;.;.

Vest4

0.85, 0.86, 0.85, 0.84

MutPred

0.62

Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);Gain of ubiquitination at Q63 (P = 0.0276);

MVP

0.95

MPC

2.2

ClinPred

0.96

GERP RS

5.3

Varity_R

0.99

gMVP

0.87

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

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