X-21440697-A-G

Variant names:

• chrX-21440697-A-G
• rs1240294498
• NM_014927.5:c.435A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_014927.5(CNKSR2):​c.435A>G​(p.Ser145Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,055,307 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: CNKSR2 NM_014927.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.195
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-21440697-A-G is Benign according to our data. Variant chrX-21440697-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3025486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.195 with no splicing effect.

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.435A>G	p.Ser145Ser	synonymous	Exon 4 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.435A>G	p.Ser145Ser	synonymous	Exon 4 of 21	NP_001162118.1	Q8WXI2-5
	CNKSR2	NM_001330770.2		c.435A>G	p.Ser145Ser	synonymous	Exon 4 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.435A>G	p.Ser145Ser	synonymous	Exon 4 of 22	ENSP00000368824.3	Q8WXI2-1
	CNKSR2	ENST00000425654.7	TSL:1	c.435A>G	p.Ser145Ser	synonymous	Exon 4 of 21	ENSP00000397906.2	Q8WXI2-5
	CNKSR2	ENST00000279451.9	TSL:1	c.435A>G	p.Ser145Ser	synonymous	Exon 4 of 20	ENSP00000279451.5	A0A2U3TZH5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000617 AC: 1 AN: 161983 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1055307 Hom.: 0 Cov.: 21 AF XY: 0.00000304 AC XY: 1 AN XY: 328855

African (AFR) AF: 0.00 AC: 0 AN: 25043

American (AMR) AF: 0.0000305 AC: 1 AN: 32779

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18641

East Asian (EAS) AF: 0.00 AC: 0 AN: 29097

South Asian (SAS) AF: 0.00 AC: 0 AN: 49604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39845

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3933

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 811898

Other (OTH) AF: 0.00 AC: 0 AN: 44467

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.3
DANN	Benign	0.76
PhyloP100		0.20
PromoterAI		0.020	Neutral

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: rs1240294498; hg19: chrX-21458815; COSMIC: COSV54249129; COSMIC: COSV54249129;