chr1-26183826-C-G

Position:

• chr1-26183826-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006314.3(CNKSR1):​c.851C>G​(p.Pro284Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,419,388 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (35 hom.)
• Consequence: CNKSR1 NM_006314.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.436

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039511323).
• BP6: Variant 1-26183826-C-G is Benign according to our data. Variant chr1-26183826-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 725931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR1	NM_006314.3	c.851C>G	p.Pro284Arg	missense_variant	9/21	ENST00000361530.11	NP_006305.2
CNKSR1	NM_001297647.2	c.872C>G	p.Pro291Arg	missense_variant	9/21		NP_001284576.1
CNKSR1	NM_001297648.2	c.77C>G	p.Pro26Arg	missense_variant	9/21		NP_001284577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR1	ENST00000361530.11	c.851C>G	p.Pro284Arg	missense_variant	9/21	1	NM_006314.3	ENSP00000354609.6

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 531 AN: 135848 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000503

Gnomad ASJ AF: 0.00789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000271

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00428

GnomAD3 exomes AF: 0.00470 AC: 1165 AN: 248046 Hom.: 11 AF XY: 0.00454 AC XY: 611 AN XY: 134610

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00790

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00369 AC: 4731 AN: 1283408 Hom.: 35 Cov.: 29 AF XY: 0.00379 AC XY: 2432 AN XY: 640914

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000595

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000734

Gnomad4 SAS exome AF: 0.000857

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00390 AC: 531 AN: 135980 Hom.: 1 Cov.: 28 AF XY: 0.00404 AC XY: 266 AN XY: 65854

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000502

Gnomad4 ASJ AF: 0.00789

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000270

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.00476

Gnomad4 OTH AF: 0.00423

Alfa AF: 0.00531 Hom.: 2

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00500 AC: 607

EpiCase AF: 0.00420

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CNKSR1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.20
DEOGEN2	Benign	0.0071	.;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.48	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.090	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.88	.;P;.
Vest4		0.19
MVP		0.21
MPC		0.23
ClinPred		0.014	T
GERP RS		0.70
Varity_R		0.041
gMVP		0.17

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

Other links and lift over

dbSNP: rs149069703; hg19: chr1-26510317; COSMIC: COSV99052540; COSMIC: COSV99052540;