22-28735141-T-C

Variant names:

• chr22-28735141-T-C
• rs1807609
• NM_007194.4:c.-6-414A>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.-6-414A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 151,780 control chromosomes in the GnomAD database, including 35,642 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 0.68 (35642 hom., cov: 31)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 11 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=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.819 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.-6-414A>G		intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.-6-414A>G		intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.-6-414A>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.-6-414A>G		intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.-6-414A>G		intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000416671.5	TSL:1	n.-6-414A>G		intron	N/A	ENSP00000402225.1	C9JFD7

Frequencies

GnomAD3 genomes AF: 0.680 AC: 103068 AN: 151662 Hom.: 35626 Cov.: 31

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.799

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.701

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

GnomAD4 genome AF: 0.679 AC: 103127 AN: 151780 Hom.: 35642 Cov.: 31 AF XY: 0.683 AC XY: 50690 AN XY: 74184

African (AFR) AF: 0.563 AC: 23249 AN: 41314

American (AMR) AF: 0.653 AC: 9933 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2857 AN: 3472

East Asian (EAS) AF: 0.786 AC: 4062 AN: 5170

South Asian (SAS) AF: 0.841 AC: 4055 AN: 4824

European-Finnish (FIN) AF: 0.735 AC: 7728 AN: 10514

Middle Eastern (MID) AF: 0.805 AC: 235 AN: 292

European-Non Finnish (NFE) AF: 0.720 AC: 48903 AN: 67956

Other (OTH) AF: 0.697 AC: 1469 AN: 2108

Alfa AF: 0.623 Hom.: 1948

Bravo AF: 0.666

Asia WGS AF: 0.805 AC: 2801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-1.3
PromoterAI		-0.0048	Neutral
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: rs1807609; hg19: chr22-29131129; COSMIC: COSV60415880; COSMIC: COSV60415880;