chr1-26183819-AC-A

Variant names:

• chr1-26183819-AC-A
• rs781114848
• NM_006314.3:c.851delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006314.3(CNKSR1):​c.851delC​(p.Pro284HisfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0561 in 1,335,818 control chromosomes in the GnomAD database, including 2,058 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.034 (101 hom., cov: 28)
  • Exomes 𝑓: 0.058 (1957 hom.)
• Consequence: CNKSR1 NM_006314.3 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-26183819-AC-A is Benign according to our data. Variant chr1-26183819-AC-A is described in ClinVar as Benign. ClinVar VariationId is 252663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

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.851delC	p.Pro284HisfsTer74	frameshift	Exon 9 of 21	NP_006305.2	Q53GM7
	CNKSR1	NM_001297647.2		c.872delC	p.Pro291HisfsTer74	frameshift	Exon 9 of 21	NP_001284576.1	Q969H4-1
	CNKSR1	NM_001297648.2		c.77delC	p.Pro26HisfsTer74	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.851delC	p.Pro284HisfsTer74	frameshift	Exon 9 of 21	ENSP00000354609.6	Q969H4-2
	CNKSR1	ENST00000374253.9	TSL:1	c.872delC	p.Pro291HisfsTer74	frameshift	Exon 9 of 21	ENSP00000363371.5	Q969H4-1
	CNKSR1	ENST00000878394.1		c.872delC	p.Pro291HisfsTer58	frameshift	Exon 9 of 21	ENSP00000548453.1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 4146 AN: 120542 Hom.: 101 Cov.: 28

Gnomad AFR AF: 0.00865

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.00376

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0274

GnomAD2 exomes AF: 0.0332 AC: 8223 AN: 247884 AF XY: 0.0334

Gnomad AFR exome AF: 0.00819

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0582 AC: 70784 AN: 1215220 Hom.: 1957 Cov.: 29 AF XY: 0.0566 AC XY: 34315 AN XY: 606542

African (AFR) AF: 0.00923 AC: 242 AN: 26222

American (AMR) AF: 0.0159 AC: 613 AN: 38450

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 499 AN: 18226

East Asian (EAS) AF: 0.000147 AC: 3 AN: 20372

South Asian (SAS) AF: 0.0121 AC: 1001 AN: 82998

European-Finnish (FIN) AF: 0.0556 AC: 2089 AN: 37554

Middle Eastern (MID) AF: 0.00652 AC: 30 AN: 4602

European-Non Finnish (NFE) AF: 0.0676 AC: 63628 AN: 941130

Other (OTH) AF: 0.0587 AC: 2679 AN: 45666

GnomAD4 genome AF: 0.0344 AC: 4145 AN: 120598 Hom.: 101 Cov.: 28 AF XY: 0.0316 AC XY: 1826 AN XY: 57768

African (AFR) AF: 0.00864 AC: 277 AN: 32074

American (AMR) AF: 0.0169 AC: 201 AN: 11876

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 50 AN: 3000

East Asian (EAS) AF: 0.00 AC: 0 AN: 3488

South Asian (SAS) AF: 0.0131 AC: 38 AN: 2910

European-Finnish (FIN) AF: 0.0368 AC: 260 AN: 7062

Middle Eastern (MID) AF: 0.00413 AC: 1 AN: 242

European-Non Finnish (NFE) AF: 0.0567 AC: 3258 AN: 57490

Other (OTH) AF: 0.0272 AC: 45 AN: 1654

Alfa AF: 0.00546 Hom.: 10

EpiCase AF: 0.0461

EpiControl AF: 0.0460

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=36/164	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: rs781114848; hg19: chr1-26510310; COSMIC: COSV64163320; COSMIC: COSV64163320;