X-21426619-C-G

Variant names:

• chrX-21426619-C-G
• rs749730618
• NM_014927.5:c.187C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014927.5(CNKSR2):​c.187C>G​(p.Gln63Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNKSR2	NM_014927.5	c.187C>G	p.Gln63Glu	missense_variant	Exon 2 of 22	ENST00000379510.5	NP_055742.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNKSR2	ENST00000379510.5	c.187C>G	p.Gln63Glu	missense_variant	Exon 2 of 22	1	NM_014927.5	ENSP00000368824.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000574 AC: 1 AN: 174183 Hom.: 0 AF XY: 0.0000168 AC XY: 1 AN XY: 59419

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1093585 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 359635

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000291

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;.;.;.;.;.;.;.;.;.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.9	H;.;H;.;H;.;.;.;.;.;H;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	.;.;D;.;D;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	.;.;D;.;D;D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;D;.;.;.;.;D;.;.
Polyphen		1.0	.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.85, 0.87, 0.87, 0.86
MutPred		0.66		Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);Gain of phosphorylation at S58 (P = 0.1471);
MVP		0.94
MPC		2.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.99
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

LitVar

Other links and lift over

dbSNP: rs749730618; hg19: chrX-21444737;