rs554125982

Variant names:

• chrX-21432746-A-G
• rs554125982
• NM_014927.5:c.363A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_014927.5(CNKSR2):​c.363A>G​(p.Pro121Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,271 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 7 hem.)
• Consequence: CNKSR2 NM_014927.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.820
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-21432746-A-G is Benign according to our data. Variant chrX-21432746-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2660143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.82 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 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.363A>G	p.Pro121Pro	synonymous	Exon 3 of 22	NP_055742.2
	CNKSR2	NM_001168647.3		c.363A>G	p.Pro121Pro	synonymous	Exon 3 of 21	NP_001162118.1	Q8WXI2-5
	CNKSR2	NM_001330770.2		c.363A>G	p.Pro121Pro	synonymous	Exon 3 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.363A>G	p.Pro121Pro	synonymous	Exon 3 of 22	ENSP00000368824.3	Q8WXI2-1
	CNKSR2	ENST00000425654.7	TSL:1	c.363A>G	p.Pro121Pro	synonymous	Exon 3 of 21	ENSP00000397906.2	Q8WXI2-5
	CNKSR2	ENST00000279451.9	TSL:1	c.363A>G	p.Pro121Pro	synonymous	Exon 3 of 20	ENSP00000279451.5	A0A2U3TZH5

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 6 AN: 111673 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000562

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.0000221 AC: 4 AN: 181394 AF XY: 0.0000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000734

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097544 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363038

African (AFR) AF: 0.00 AC: 0 AN: 26347

American (AMR) AF: 0.00 AC: 0 AN: 35081

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30141

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54027

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4127

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841862

Other (OTH) AF: 0.0000434 AC: 2 AN: 46071

GnomAD4 genome AF: 0.0000537 AC: 6 AN: 111727 Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2 AN XY: 33903

African (AFR) AF: 0.00 AC: 0 AN: 30804

American (AMR) AF: 0.00 AC: 0 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.000564 AC: 2 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53128

Other (OTH) AF: 0.000656 AC: 1 AN: 1525

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

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	-0.49
CADD	Benign	9.9
DANN	Benign	0.76
PhyloP100		0.82
Mutation Taster		=99/1	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: rs554125982; hg19: chrX-21450864;