X-21432661-A-G

Position:

• chrX-21432661-A-G

Variant summary

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

The NM_014927.5(CNKSR2):​c.278A>G​(p.Asn93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000922 in 1,084,324 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: CNKSR2 NM_014927.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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=0.34675905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNKSR2	NM_014927.5	c.278A>G	p.Asn93Ser	missense_variant	3/22	ENST00000379510.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNKSR2	ENST00000379510.5	c.278A>G	p.Asn93Ser	missense_variant	3/22	1	NM_014927.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084324 Hom.: 0 Cov.: 27 AF XY: 0.00000285 AC XY: 1 AN XY: 351404

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: 0.0000191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;.;.;.;.;.;.;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N;.;N;.;.;.;.;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.4	.;.;N;.;N;N;.;.;.;.;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.51	.;.;T;.;T;T;.;.;.;.;T;.;.
Sift4G	Benign	0.24	.;.;T;.;T;T;.;.;.;.;T;.;.
Polyphen		0.041	.;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.50, 0.32, 0.37, 0.49
MutPred		0.48		Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);Gain of ubiquitination at K91 (P = 0.0725);
MVP		0.80
MPC		0.73
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.35
gMVP		0.69

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: rs1167304415; hg19: chrX-21450779;