X-21426505-G-A

Position:

• chrX-21426505-G-A

Variant summary

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

The NM_014927.5(CNKSR2):​c.73G>A​(p.Asp25Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 9.52

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.73G>A	p.Asp25Asn	missense_variant	2/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.73G>A	p.Asp25Asn	missense_variant	2/22	1	NM_014927.5	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Houge type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 12, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3,BP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	.;.;.;.;.;.;.;.;.;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.6	M;.;M;.;M;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	.;.;D;.;D;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	.;.;D;.;T;T;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;D;.;.;.;.;D;.;.
Polyphen		0.76	.;.;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.68, 0.68, 0.74, 0.66
MutPred		0.44		Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);Gain of MoRF binding (P = 0.0804);
MVP		0.92
MPC		0.85
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.46

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: rs2090566346; hg19: chrX-21444623;