Variant X-21470772-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_014927.5(CNKSR2):c.526A>T(p.Thr176Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000112 in 892,776 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000011 ( 0 hom. 0 hem. )

Consequence

CNKSR2
NM_014927.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11

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 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3320495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5 linkuse as main transcript	c.526A>T	p.Thr176Ser	missense_variant	5/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5 linkuse as main transcript	c.526A>T	p.Thr176Ser	missense_variant	5/22	1	NM_014927.5	P1	Q8WXI2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000112

AC:

AN:

892776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

250476

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:

0.00000146

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.526A>T (p.T176S) alteration is located in exon 5 (coding exon 5) of the CNKSR2 gene. This alteration results from a A to T substitution at nucleotide position 526, causing the threonine (T) at amino acid position 176 to be replaced by a serine (S). 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

0.16

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

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

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.33

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;L;.;L;.;.;.;.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

.;.;N;.;N;N;.;.;.;.;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.43

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

Sift4G

Benign

0.33

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

Polyphen

0.022

.;.;.;.;.;.;.;.;.;.;B;.;.

Vest4

0.56, 0.58, 0.48, 0.47

MutPred

0.55

Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);Loss of phosphorylation at T176 (P = 0.2016);

MVP

0.70

MPC

0.85

ClinPred

0.80

GERP RS

5.5

Varity_R

0.46

gMVP

0.47

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over