22-28736401-G-C

Variant names:

• chr22-28736401-G-C
• rs5762763
• NM_007194.4:c.-6-1674C>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.-6-1674C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,046 control chromosomes in the GnomAD database, including 6,991 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 (6991 hom., cov: 32)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.307
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.-6-1674C>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.-6-1674C>G		intron_variant	Intron 1 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40834 AN: 151928 Hom.: 6995 Cov.: 32

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.268 AC: 40814 AN: 152046 Hom.: 6991 Cov.: 32 AF XY: 0.265 AC XY: 19676 AN XY: 74306

African (AFR) AF: 0.0681 AC: 2826 AN: 41500

American (AMR) AF: 0.231 AC: 3523 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1190 AN: 3470

East Asian (EAS) AF: 0.193 AC: 998 AN: 5174

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4818

European-Finnish (FIN) AF: 0.328 AC: 3465 AN: 10556

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.381 AC: 25924 AN: 67956

Other (OTH) AF: 0.293 AC: 619 AN: 2114

Alfa AF: 0.193 Hom.: 466

Bravo AF: 0.251

Asia WGS AF: 0.282 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.78
PhyloP100		-0.31
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: rs5762763; hg19: chr22-29132389;