X-21426608-G-T

Variant names:

• chrX-21426608-G-T
• rs1397199866
• NM_014927.5:c.176G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014927.5(CNKSR2):​c.176G>T​(p.Arg59Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.66

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNKSR2	NM_014927.5	c.176G>T	p.Arg59Leu	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.176G>T	p.Arg59Leu	missense_variant	Exon 2 of 22	1	NM_014927.5	ENSP00000368824.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000572 AC: 1 AN: 174809 Hom.: 0 AF XY: 0.0000166 AC XY: 1 AN XY: 60109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094045 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 360069

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: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;.;.;.;.;.;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;M;.;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	.;.;D;.;D;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.014	.;.;D;.;D;D;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0080	.;.;D;.;D;D;.;.;.;.;D;.;.
Polyphen		0.44	.;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.66, 0.67, 0.69, 0.66
MutPred		0.53		Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);
MVP		0.89
MPC		1.7
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.91
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: rs1397199866; hg19: chrX-21444726;