rs5762765

Variant names:

• chr22-28737045-G-C
• rs5762765
• NM_007194.4:c.-6-2318C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007194.4(CHEK2):​c.-6-2318C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 151,952 control chromosomes in the GnomAD database, including 6,996 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6996 hom., cov: 30)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 9 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. 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
	CHEK2	NM_007194.4	MANE Select	c.-6-2318C>G		intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.-6-2318C>G		intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.-6-2318C>G		intron	N/A	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.-6-2318C>G		intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.-6-2318C>G		intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000416671.5	TSL:1	n.-6-2318C>G		intron	N/A	ENSP00000402225.1	C9JFD7

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41074 AN: 151834 Hom.: 6998 Cov.: 30

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.270 AC: 41068 AN: 151952 Hom.: 6996 Cov.: 30 AF XY: 0.266 AC XY: 19751 AN XY: 74288

African (AFR) AF: 0.0757 AC: 3140 AN: 41502

American (AMR) AF: 0.234 AC: 3565 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3470

East Asian (EAS) AF: 0.194 AC: 999 AN: 5160

South Asian (SAS) AF: 0.345 AC: 1662 AN: 4812

European-Finnish (FIN) AF: 0.330 AC: 3480 AN: 10530

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25847 AN: 67932

Other (OTH) AF: 0.302 AC: 636 AN: 2106

Alfa AF: 0.317 Hom.: 1056

Bravo AF: 0.253

Asia WGS AF: 0.281 AC: 980 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.25
DANN	Benign	0.24
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs5762765; hg19: chr22-29133033; COSMIC: COSV53263104; COSMIC: COSV53263104;