X-21426551-G-A

Position:

• chrX-21426551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014927.5(CNKSR2):​c.119G>A​(p.Ser40Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26598823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5	c.119G>A	p.Ser40Asn	missense_variant	2/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.119G>A	p.Ser40Asn	missense_variant	2/22	1	NM_014927.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.119G>A (p.S40N) alteration is located in exon 2 (coding exon 2) of the CNKSR2 gene. This alteration results from a G to A substitution at nucleotide position 119, causing the serine (S) at amino acid position 40 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.20	.;.;.;.;.;.;.;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N;.;N;.;N;.;.;.;.;.;N;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.66	.;.;N;.;N;N;.;.;.;.;N;.;.
REVEL	Benign	0.051
Sift	Benign	0.63	.;.;T;.;T;T;.;.;.;.;T;.;.
Sift4G	Benign	1.0	.;.;T;.;T;T;.;.;.;.;T;.;.
Polyphen		0.0020	.;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.15, 0.15, 0.14, 0.13
MutPred		0.35		Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);Loss of glycosylation at S40 (P = 0.0305);
MVP		0.59
MPC		0.78
ClinPred		0.59	D
GERP RS		4.5
Varity_R		0.35
gMVP		0.33

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-21444669;