chrX-21426508-T-C

Position:

• chrX-21426508-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_014927.5(CNKSR2):​c.76T>C​(p.Cys26Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR2	NM_014927.5	c.76T>C	p.Cys26Arg	missense_variant	2/22	ENST00000379510.5	NP_055742.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR2	ENST00000379510.5	c.76T>C	p.Cys26Arg	missense_variant	2/22	1	NM_014927.5	ENSP00000368824.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Houge type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;.;.;.;.;.;.;.;.;.;D;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;M;.;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.0	.;.;D;.;D;D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	.;.;D;.;D;D;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0020	.;.;D;.;D;D;.;.;.;.;D;.;.
Polyphen		0.99	.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.78, 0.79, 0.83, 0.80
MutPred		0.58		Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);
MVP		0.92
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.85

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-21444626;