rs2236142

Positions:

• chr22-28741956-G-C
• chr22-28741956-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000416671.5(CHEK2):​c.-194C>G variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 846,056 control chromosomes in the GnomAD database, including 176,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33322 hom., cov: 32)
  • Exomes 𝑓: 0.63 (143301 hom.)
• Consequence: CHEK2 ENST00000416671.5 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.264

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-28741956-G-C is Benign according to our data. Variant chr22-28741956-G-C is described in ClinVar as [Benign]. Clinvar id is 1268378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000416671.5	c.-194C>G		5_prime_UTR_variant, NMD_transcript_variant	1/16	1		ENSP00000402225

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99757 AN: 151974 Hom.: 33304 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.588

GnomAD4 exome AF: 0.633 AC: 439625 AN: 693964 Hom.: 143301 Cov.: 9 AF XY: 0.625 AC XY: 222022 AN XY: 355154

Gnomad4 AFR exome AF: 0.715

Gnomad4 AMR exome AF: 0.564

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.685

Gnomad4 NFE exome AF: 0.678

Gnomad4 OTH exome AF: 0.614

GnomAD4 genome AF: 0.656 AC: 99819 AN: 152092 Hom.: 33322 Cov.: 32 AF XY: 0.651 AC XY: 48419 AN XY: 74360

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.496

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.585

Alfa AF: 0.680 Hom.: 4425

Bravo AF: 0.650

Asia WGS AF: 0.385 AC: 1339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.5
DANN	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2236142; hg19: chr22-29137944; COSMIC: COSV53263634;