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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNKSR1	NM_006314.3	c.851delC	p.Pro284HisfsTer74	frameshift_variant	Exon 9 of 21	ENST00000361530.11	NP_006305.2
CNKSR1	NM_001297647.2	c.872delC	p.Pro291HisfsTer74	frameshift_variant	Exon 9 of 21		NP_001284576.1
CNKSR1	NM_001297648.2	c.77delC	p.Pro26HisfsTer74	frameshift_variant	Exon 9 of 21		NP_001284577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNKSR1	ENST00000361530.11	c.851delC	p.Pro284HisfsTer74	frameshift_variant	Exon 9 of 21	1	NM_006314.3	ENSP00000354609.6

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

Gnomad4 AFR exome AF: 0.00923 AC: 242 AN: 26222

Gnomad4 AMR exome AF: 0.0159 AC: 613 AN: 38450

Gnomad4 ASJ exome AF: 0.0274 AC: 499 AN: 18226

Gnomad4 EAS exome AF: 0.000147 AC: 3 AN: 20372

Gnomad4 SAS exome AF: 0.0121 AC: 1001 AN: 82998

Gnomad4 FIN exome AF: 0.0556 AC: 2089 AN: 37554

Gnomad4 NFE exome AF: 0.0676 AC: 63628 AN: 941130

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.00864 AC: 0.00863628 AN: 0.00863628

Gnomad4 AMR AF: 0.0169 AC: 0.0169249 AN: 0.0169249

Gnomad4 ASJ AF: 0.0167 AC: 0.0166667 AN: 0.0166667

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0131 AC: 0.0130584 AN: 0.0130584

Gnomad4 FIN AF: 0.0368 AC: 0.0368168 AN: 0.0368168

Gnomad4 NFE AF: 0.0567 AC: 0.0566707 AN: 0.0566707

Gnomad4 OTH AF: 0.0272 AC: 0.0272068 AN: 0.0272068

Alfa AF: 0.00546 Hom.: 10

EpiCase AF: 0.0461

EpiControl AF: 0.0460

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2C Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous c.851delC variant in CNKSR1 has been identified in an individual with intellectual disability in the literature (PMID: 21937992). However, this variant is classified as benign for autosomal recessive intellectual disability because it has been identified in >5% of European (non-Finnish) chromosomes and 108 total homozygotes, by ExAC (http://gnomad.broadinstitute.org/). -

not provided Benign:1

Dec 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30450701, 27535533, 21937992) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs781114848; hg19: chr1-26510310; COSMIC: COSV64163320; COSMIC: COSV64163320;