1-26177584-G-A

Position:

• chr1-26177584-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006314.3(CNKSR1):​c.37G>A​(p.Ala13Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNKSR1 NM_006314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR1	NM_006314.3	c.37G>A	p.Ala13Thr	missense_variant	1/21	ENST00000361530.11	NP_006305.2
CNKSR1	NM_001297647.2	c.37G>A	p.Ala13Thr	missense_variant	1/21		NP_001284576.1
CNKSR1	NM_001297648.2	c.-733G>A		5_prime_UTR_variant	1/21		NP_001284577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR1	ENST00000361530.11	c.37G>A	p.Ala13Thr	missense_variant	1/21	1	NM_006314.3	ENSP00000354609.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.37G>A (p.A13T) alteration is located in exon 1 (coding exon 1) of the CNKSR1 gene. This alteration results from a G to A substitution at nucleotide position 37, causing the alanine (A) at amino acid position 13 to be replaced by a threonine (T). 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	0.20
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0090	.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.075	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.20
Sift	Benign	0.31	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.98	.;D
Vest4		0.30
MutPred		0.59		Gain of ubiquitination at K11 (P = 0.0817);Gain of ubiquitination at K11 (P = 0.0817);
MVP		0.33
MPC		0.29
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-26504075;