Variant X-21440698-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_014927.5(CNKSR2):c.436C>G(p.Pro146Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000257 in 1,169,049 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., 0 hem., cov: 22)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

CNKSR2
NM_014927.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

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 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5 linkuse as main transcript	c.436C>G	p.Pro146Ala	missense_variant	4/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5 linkuse as main transcript	c.436C>G	p.Pro146Ala	missense_variant	4/22	1	NM_014927.5	P1	Q8WXI2-1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33602

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000960

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

GnomAD4 exome

AF:

0.00000189

AC:

AN:

1057733

Hom.:

Cov.:

AF XY:

0.00000302

AC XY:

AN XY:

330763

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:

0.00000246

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33602

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000960

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

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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

0.90

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.93

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

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.2

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

REVEL

Uncertain

0.52

Sift

Benign

0.10

.;.;T;.;D;D;.;.;.;.;T;.;.

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.76, 0.71, 0.76, 0.74

MutPred

0.86

Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);Gain of catalytic residue at P146 (P = 0.0526);

MVP

0.68

MPC

1.9

ClinPred

0.99

GERP RS

5.4

Varity_R

0.60

gMVP

0.92

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