X-21426560-A-G

Position:

• chrX-21426560-A-G

Variant summary

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

The NM_014927.5(CNKSR2):​c.128A>G​(p.Gln43Arg) 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: 7.08

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.128A>G	p.Gln43Arg	missense_variant	2/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.128A>G	p.Gln43Arg	missense_variant	2/22	1	NM_014927.5	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Mar 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;.;.;.;.;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.;L;.;L;.;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	.;.;N;.;N;N;.;.;.;.;N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.14	.;.;T;.;T;T;.;.;.;.;T;.;.
Sift4G	Benign	0.15	.;.;T;.;T;T;.;.;.;.;T;.;.
Polyphen		0.012	.;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.45, 0.47, 0.37, 0.69
MutPred		0.74		Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);Loss of ubiquitination at K38 (P = 0.0396);
MVP		0.98
MPC		0.90
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.67
gMVP		0.78

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-21444678; COSMIC: COSV105849244; COSMIC: COSV105849244;