Variant chr1-26183209-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001297648.2(CNKSR1):c.-138C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CNKSR1
NM_001297648.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.273

Variant links:

Genes affected

CNKSR1 (HGNC:19700): (connector enhancer of kinase suppressor of Ras 1) This gene encodes a protein containing several motifs involved in protein-protein interaction, including PDZ, PH (Pleckstrin homology), and SAM (sterile alpha motif) domains. The encoded protein acts as a scaffold component for receptor tyrosine kinase signaling and may mediate crosstalk between different signaling pathways. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CNKSR1 links:

CNKSR1 (HGNC:):

CNKSR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17164621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR1	NM_006314.3 linkuse as main transcript	c.637C>G	p.His213Asp	missense_variant	7/21	ENST00000361530.11	NP_006305.2	Q969H4-2Q53GM7
CNKSR1	NM_001297648.2 linkuse as main transcript	c.-138C>G		5_prime_UTR_premature_start_codon_gain_variant	7/21		NP_001284577.1	Q969H4G3V160B4DL25
CNKSR1	NM_001297647.2 linkuse as main transcript	c.637C>G	p.His213Asp	missense_variant	7/21		NP_001284576.1	Q969H4-1B4DL25
CNKSR1	NM_001297648.2 linkuse as main transcript	c.-138C>G		5_prime_UTR_variant	7/21		NP_001284577.1	Q969H4G3V160B4DL25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR1	ENST00000361530.11 linkuse as main transcript	c.637C>G	p.His213Asp	missense_variant	7/21	1	NM_006314.3	ENSP00000354609.6		Q969H4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251324

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727180

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

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

May 30, 2024

The c.637C>G (p.H213D) alteration is located in exon 7 (coding exon 7) of the CNKSR1 gene. This alteration results from a C to G substitution at nucleotide position 637, causing the histidine (H) at amino acid position 213 to be replaced by an aspartic acid (D). 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

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0099

.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.011

D;D

Sift4G

Benign

0.39

T;T

Polyphen

0.45

.;P

Vest4

0.43

MutPred

0.22

Gain of disorder (P = 0.1042);Gain of disorder (P = 0.1042);

MVP

0.15

MPC

0.29

ClinPred

0.094

GERP RS

2.4

Varity_R

0.15

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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