X-21426611-T-C

Position:

• chrX-21426611-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014927.5(CNKSR2):​c.179T>C​(p.Ile60Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5	c.179T>C	p.Ile60Thr	missense_variant	2/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.179T>C	p.Ile60Thr	missense_variant	2/22	1	NM_014927.5	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.179T>C (p.I60T) alteration is located in exon 2 (coding exon 2) of the CNKSR2 gene. This alteration results from a T to C substitution at nucleotide position 179, causing the isoleucine (I) at amino acid position 60 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. 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	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;.;.;.;.;.;.;.;.;D;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.9	M;.;M;.;M;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	.;.;D;.;D;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	.;.;D;.;D;D;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0050	.;.;D;.;D;D;.;.;.;.;D;.;.
Polyphen		0.95	.;.;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.75, 0.79, 0.79, 0.77
MutPred		0.59		Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.94
gMVP		0.72

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.

Other links and lift over

hg19: chrX-21444729; COSMIC: COSV54255644; COSMIC: COSV54255644;