rs757776373

Variant names:

• chrX-21426624-A-G
• rs757776373
• NM_014927.5:c.192A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014927.5(CNKSR2):​c.192A>G​(p.Glu64Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,204,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000081 (0 hom. 31 hem.)
• Consequence: CNKSR2 NM_014927.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked, syndromic, Houge type

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-21426624-A-G is Benign according to our data. Variant chrX-21426624-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195303.
• BP7: Synonymous conserved (PhyloP=-0.029 with no splicing effect.
• BS2: High AC in GnomAd4 at 11 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014927.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	NM_014927.5	MANE Select	c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 21	NP_001162118.1	Q8WXI2-5
	CNKSR2	NM_001330770.2		c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 21	NP_001317699.1	A0A2R8Y7A1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR2	ENST00000379510.5	TSL:1 MANE Select	c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 22	ENSP00000368824.3	Q8WXI2-1
	CNKSR2	ENST00000425654.7	TSL:1	c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 21	ENSP00000397906.2	Q8WXI2-5
	CNKSR2	ENST00000279451.9	TSL:1	c.192A>G	p.Glu64Glu	synonymous	Exon 2 of 20	ENSP00000279451.5	A0A2U3TZH5

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 11 AN: 111698 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000347 AC: 6 AN: 172923 AF XY: 0.0000343

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000768

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 89 AN: 1093012 Hom.: 0 Cov.: 30 AF XY: 0.0000863 AC XY: 31 AN XY: 359182

African (AFR) AF: 0.0000384 AC: 1 AN: 26022

American (AMR) AF: 0.00 AC: 0 AN: 34249

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19245

East Asian (EAS) AF: 0.00 AC: 0 AN: 29740

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 53001

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4105

European-Non Finnish (NFE) AF: 0.000102 AC: 86 AN: 840282

Other (OTH) AF: 0.0000218 AC: 1 AN: 45889

GnomAD4 genome AF: 0.0000985 AC: 11 AN: 111698 Hom.: 0 Cov.: 23 AF XY: 0.0000591 AC XY: 2 AN XY: 33854

African (AFR) AF: 0.0000326 AC: 1 AN: 30704

American (AMR) AF: 0.00 AC: 0 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6057

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53164

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.2
DANN	Benign	0.63
PhyloP100		-0.029
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs757776373; hg19: chrX-21444742;