rs6528025

Variant names:

• chrX-21598242-G-C
• rs6528025
• NM_014927.5:c.1976+2847G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014927.5(CNKSR2):​c.1976+2847G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 110,590 control chromosomes in the GnomAD database, including 2,834 homozygotes. There are 4,289 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2834 hom., 4289 hem., cov: 22)
• Consequence: CNKSR2 NM_014927.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNKSR2	NM_014927.5	c.1976+2847G>C		intron_variant	Intron 17 of 21	ENST00000379510.5	NP_055742.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNKSR2	ENST00000379510.5	c.1976+2847G>C		intron_variant	Intron 17 of 21	1	NM_014927.5	ENSP00000368824.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 16192 AN: 110545 Hom.: 2831 Cov.: 22

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0608

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.00646

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.00664

Gnomad MID AF: 0.0468

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.147 AC: 16223 AN: 110590 Hom.: 2834 Cov.: 22 AF XY: 0.130 AC XY: 4289 AN XY: 32922

African (AFR) AF: 0.498 AC: 15016 AN: 30146

American (AMR) AF: 0.0606 AC: 631 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 124 AN: 2640

East Asian (EAS) AF: 0.00648 AC: 23 AN: 3552

South Asian (SAS) AF: 0.0163 AC: 43 AN: 2634

European-Finnish (FIN) AF: 0.00664 AC: 39 AN: 5874

Middle Eastern (MID) AF: 0.0512 AC: 11 AN: 215

European-Non Finnish (NFE) AF: 0.00287 AC: 152 AN: 52934

Other (OTH) AF: 0.123 AC: 184 AN: 1499

Alfa AF: 0.0888 Hom.: 563

Bravo AF: 0.168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.69
PhyloP100		0.053
Mutation Taster		=100/0	polymorphism (auto)

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: rs6528025; hg19: chrX-21616360;