Variant 6-154411062-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_173515.4(CNKSR3):c.1151C>G(p.Pro384Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CNKSR3
NM_173515.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.53

Variant links:

Genes affected

CNKSR3 (HGNC:23034): (CNKSR family member 3) Predicted to be involved in negative regulation of ERK1 and ERK2 cascade; negative regulation of peptidyl-serine phosphorylation; and positive regulation of sodium ion transport. Predicted to act upstream of or within positive regulation of sodium ion transmembrane transporter activity. Predicted to be located in apical plasma membrane and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CNKSR3 links:

ENSG00000288520 (HGNC:):

ENSG00000288520 links:

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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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR3	NM_173515.4 linkuse as main transcript	c.1151C>G	p.Pro384Arg	missense_variant	11/13	ENST00000607772.6	NP_775786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR3	ENST00000607772.6 linkuse as main transcript	c.1151C>G	p.Pro384Arg	missense_variant	11/13	1	NM_173515.4	ENSP00000475915.1		Q6P9H4-1
ENSG00000288520	ENST00000673182.1 linkuse as main transcript	c.1151C>G	p.Pro384Arg	missense_variant	11/22			ENSP00000499846.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251430

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

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:

0.0000137

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000425

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1151C>G (p.P384R) alteration is located in exon 11 (coding exon 11) of the CNKSR3 gene. This alteration results from a C to G substitution at nucleotide position 1151, causing the proline (P) at amino acid position 384 to be replaced by an arginine (R). 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

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.5

.;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.93

MutPred

0.61

Loss of sheet (P = 3e-04);.;.;

MVP

0.80

MPC

0.95

ClinPred

0.85

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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