22-28738571-G-C

Variant names:

• chr22-28738571-G-C
• rs9608698
• NM_007194.4:c.-7+3198C>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.-7+3198C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 151,990 control chromosomes in the GnomAD database, including 14,158 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 0.39 (14158 hom., cov: 32)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406
• Publications: 20 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
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

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

  Inheritance: AD 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 = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.-7+3198C>G		intron_variant	Intron 1 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.-7+3198C>G		intron_variant	Intron 1 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59267 AN: 151872 Hom.: 14163 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.390 AC: 59259 AN: 151990 Hom.: 14158 Cov.: 32 AF XY: 0.386 AC XY: 28698 AN XY: 74292

African (AFR) AF: 0.127 AC: 5272 AN: 41470

American (AMR) AF: 0.458 AC: 6987 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3464

East Asian (EAS) AF: 0.212 AC: 1096 AN: 5176

South Asian (SAS) AF: 0.216 AC: 1042 AN: 4824

European-Finnish (FIN) AF: 0.507 AC: 5348 AN: 10546

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36787 AN: 67958

Other (OTH) AF: 0.385 AC: 812 AN: 2108

Alfa AF: 0.334 Hom.: 1052

Bravo AF: 0.376

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.64
PhyloP100		0.41
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: rs9608698; hg19: chr22-29134559;