X-21532046-C-T

Variant names:

• chrX-21532046-C-T
• rs1064794022
• NM_014927.5:c.1282C>T

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.1282C>T​(p.Arg428*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CNKSR2 NM_014927.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.31
• Publications: 2 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-21532046-C-T is Pathogenic according to our data. Variant chrX-21532046-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 419657.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	NM_014927.5	MANE Select	c.1282C>T	p.Arg428*	stop_gained	Exon 11 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.1282C>T	p.Arg428*	stop_gained	Exon 11 of 21	NP_001162118.1
	CNKSR2	NM_001330770.2		c.1135C>T	p.Arg379*	stop_gained	Exon 10 of 21	NP_001317699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	ENST00000379510.5	TSL:1 MANE Select	c.1282C>T	p.Arg428*	stop_gained	Exon 11 of 22	ENSP00000368824.3
	CNKSR2	ENST00000425654.7	TSL:1	c.1282C>T	p.Arg428*	stop_gained	Exon 11 of 21	ENSP00000397906.2
	CNKSR2	ENST00000279451.9	TSL:1	c.1282C>T	p.Arg428*	stop_gained	Exon 11 of 20	ENSP00000279451.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Jul 10, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 06, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R428X variant in the CNKSR2 gene has not been reported previously as a pathogenic variantnor as a benign polymorphism, to our knowledge. This variant is predicted to cause loss of normal proteinfunction either through protein truncation or nonsense-mediated mRNA decay. The R428X variant wasnot observed in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. We interpretR428X as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		2.3
Vest4		0.44
GERP RS		4.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064794022; hg19: chrX-21550164;