NM_014927.5:c.2134C>T

Variant names:

• chrX-21606868-C-T
• rs904072058
• NM_014927.5:c.2134C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014927.5(CNKSR2):​c.2134C>T​(p.Arg712*) 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)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CNKSR2 NM_014927.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.990
• Publications: 1 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 18 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-21606868-C-T is Pathogenic according to our data. Variant chrX-21606868-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2134C>T	p.Arg712*	stop_gained	Exon 19 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.2044C>T	p.Arg682*	stop_gained	Exon 18 of 21	NP_001162118.1
	CNKSR2	NM_001330770.2		c.1987C>T	p.Arg663*	stop_gained	Exon 18 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.2134C>T	p.Arg712*	stop_gained	Exon 19 of 22	ENSP00000368824.3
	CNKSR2	ENST00000425654.7	TSL:1	c.2044C>T	p.Arg682*	stop_gained	Exon 18 of 21	ENSP00000397906.2
	CNKSR2	ENST00000279451.9	TSL:1	c.2044C>T	p.Arg682*	stop_gained	Exon 18 of 20	ENSP00000279451.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1013762 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 292856

African (AFR) AF: 0.00 AC: 0 AN: 24489

American (AMR) AF: 0.00 AC: 0 AN: 31812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18115

East Asian (EAS) AF: 0.00 AC: 0 AN: 29131

South Asian (SAS) AF: 0.00 AC: 0 AN: 47669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775389

Other (OTH) AF: 0.00 AC: 0 AN: 43195

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, X-linked, syndromic, Houge type (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.71	D
PhyloP100		0.99
Vest4		0.46
GERP RS		5.0
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: rs904072058; hg19: chrX-21624986;