1-26181903-C-G

Variant names:

• chr1-26181903-C-G
• rs780235575
• NM_006314.3:c.439C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006314.3(CNKSR1):​c.439C>G​(p.Arg147Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNKSR1 NM_006314.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

Genes affected

CNKSR1 (HGNC:19700): (connector enhancer of kinase suppressor of Ras 1) This gene encodes a protein containing several motifs involved in protein-protein interaction, including PDZ, PH (Pleckstrin homology), and SAM (sterile alpha motif) domains. The encoded protein acts as a scaffold component for receptor tyrosine kinase signaling and may mediate crosstalk between different signaling pathways. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CNKSR1 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112577856).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006314.3. 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
	CNKSR1	NM_006314.3	MANE Select	c.439C>G	p.Arg147Gly	missense	Exon 4 of 21	NP_006305.2	Q53GM7
	CNKSR1	NM_001297647.2		c.439C>G	p.Arg147Gly	missense	Exon 4 of 21	NP_001284576.1	Q969H4-1
	CNKSR1	NM_001297648.2		c.-331C>G		5_prime_UTR	Exon 4 of 21	NP_001284577.1	G3V160

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR1	ENST00000361530.11	TSL:1 MANE Select	c.439C>G	p.Arg147Gly	missense	Exon 4 of 21	ENSP00000354609.6	Q969H4-2
	CNKSR1	ENST00000374253.9	TSL:1	c.439C>G	p.Arg147Gly	missense	Exon 4 of 21	ENSP00000363371.5	Q969H4-1
	CNKSR1	ENST00000878394.1		c.439C>G	p.Arg147Gly	missense	Exon 4 of 21	ENSP00000548453.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.083
Sift	Benign	0.099	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.55		Loss of stability (P = 0.0794)
MVP		0.16
MPC		0.27
ClinPred		0.20	T
GERP RS		4.2
Varity_R		0.085
gMVP		0.31
Mutation Taster		=96/4	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: rs780235575; hg19: chr1-26508394;