X-21606868-C-T

Position:

• chrX-21606868-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014927.5(CNKSR2):​c.2134C>T​(p.Arg712Ter) 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

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 Pathogenic. Variant got 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 id is 446716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-21606868-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5	c.2134C>T	p.Arg712Ter	stop_gained	19/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.2134C>T	p.Arg712Ter	stop_gained	19/22	1	NM_014927.5	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Houge type Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 19, 2021	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	not provided	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Observed in hemizygous state in two brothers with severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS), developmental delay and ADHD; in heterozygous state in a sister with childhood epilepsy with centrotemporal spikes, mild developmental delay and learning difficulties; and in heterozygous state in the mother with febrile seizures (Damiano et al., 2017); This variant is associated with the following publications: (PMID: 31414730, 32245427, 28098945) -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.46, 0.45, 0.49
GERP RS		5.0

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: rs904072058; hg19: chrX-21624986;