chrX-21374954-G-A

Variant names:

• chrX-21374954-G-A
• NM_014927.5:c.57G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014927.5(CNKSR2):​c.57G>A​(p.Trp19*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: CNKSR2 NM_014927.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.09
• Publications: 0 publications found

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]

CNKSR2 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked, syndromic, Houge type

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-21374954-G-A is Pathogenic according to our data. Variant chrX-21374954-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3602104.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014927.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	NM_014927.5	MANE Select	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.57G>A	p.Trp19*	stop_gained	Exon 1 of 21	NP_001162118.1	Q8WXI2-5
	CNKSR2	NM_001330770.2		c.57G>A	p.Trp19*	stop_gained	Exon 1 of 21	NP_001317699.1	A0A2R8Y7A1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	ENST00000379510.5	TSL:1 MANE Select	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 22	ENSP00000368824.3	Q8WXI2-1
	CNKSR2	ENST00000425654.7	TSL:1	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 21	ENSP00000397906.2	Q8WXI2-5
	CNKSR2	ENST00000279451.9	TSL:1	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 20	ENSP00000279451.5	A0A2U3TZH5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked, syndromic, Houge type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		6.1
Vest4		0.29
GERP RS		4.8
PromoterAI		-0.086	Neutral
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chrX-21393072; COSMIC: COSV99670198; COSMIC: COSV99670198;