1-26183819-ACC-ACCCC

Variant names:

• chr1-26183819-A-ACC
• rs781114848
• NM_006314.3:c.850_851dupCC

Variant summary

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

The NM_006314.3(CNKSR1):​c.850_851dupCC​(p.Gln285HisfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000247 in 1,215,618 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: CNKSR1 NM_006314.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.850_851dupCC	p.Gln285HisfsTer74	frameshift	Exon 9 of 21	NP_006305.2	Q53GM7
	CNKSR1	NM_001297647.2		c.871_872dupCC	p.Gln292HisfsTer74	frameshift	Exon 9 of 21	NP_001284576.1	Q969H4-1
	CNKSR1	NM_001297648.2		c.76_77dupCC	p.Gln27HisfsTer74	frameshift	Exon 9 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.850_851dupCC	p.Gln285HisfsTer74	frameshift	Exon 9 of 21	ENSP00000354609.6	Q969H4-2
	CNKSR1	ENST00000374253.9	TSL:1	c.871_872dupCC	p.Gln292HisfsTer74	frameshift	Exon 9 of 21	ENSP00000363371.5	Q969H4-1
	CNKSR1	ENST00000878394.1		c.871_872dupCC	p.Gln292HisfsTer58	frameshift	Exon 9 of 21	ENSP00000548453.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247884 AF XY: 0.00000743

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000247 AC: 3 AN: 1215618 Hom.: 0 Cov.: 29 AF XY: 0.00000165 AC XY: 1 AN XY: 606746

African (AFR) AF: 0.00 AC: 0 AN: 26222

American (AMR) AF: 0.00 AC: 0 AN: 38450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18234

East Asian (EAS) AF: 0.00 AC: 0 AN: 20374

South Asian (SAS) AF: 0.00 AC: 0 AN: 83000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 0.00000319 AC: 3 AN: 941498

Other (OTH) AF: 0.00 AC: 0 AN: 45674

GnomAD4 genome Cov.: 28

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=26/174	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781114848; hg19: chr1-26510310;