Variant X-21426608-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_014927.5(CNKSR2):c.176G>A(p.Arg59His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,205,590 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CNKSR2
NM_014927.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNKSR2. . Gene score misZ 3.6053 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked complex neurodevelopmental disorder, intellectual disability, X-linked, syndromic, Houge type, non-syndromic X-linked intellectual disability, undetermined early-onset epileptic encephalopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5 linkuse as main transcript	c.176G>A	p.Arg59His	missense_variant	2/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5 linkuse as main transcript	c.176G>A	p.Arg59His	missense_variant	2/22	1	NM_014927.5	P1	Q8WXI2-1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33724

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000377

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:

0.00000572

AC:

AN:

174809

Hom.:

AF XY:

0.0000166

AC XY:

AN XY:

60109

show subpopulations

Gnomad AFR exome

AF:

0.0000795

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:

0.00000183

AC:

AN:

1094042

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

360068

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:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33724

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000377

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

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Houge type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Aug 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

.;.;.;.;.;.;.;.;.;.;T;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.61

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

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.0

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

REVEL

Uncertain

0.32

Sift

Uncertain

0.012

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

Sift4G

Uncertain

0.0070

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

Polyphen

0.98

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

Vest4

0.48, 0.48, 0.50, 0.46

MutPred

0.48

Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);Gain of disorder (P = 0.0871);

MVP

0.88

MPC

2.0

ClinPred

0.94

GERP RS

4.4

Varity_R

0.76

gMVP

0.66

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