NM_007194.4:c.684-551T>A

Variant names:

• chr22-28712568-A-T
• rs9620817
• NM_007194.4:c.684-551T>A

Variant summary

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

The NM_007194.4(CHEK2):​c.684-551T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 152,154 control chromosomes in the GnomAD database, including 612 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 0.084 (612 hom., cov: 33)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.735
• Publications: 13 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.097 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.684-551T>A		intron	N/A	NP_009125.1
	CHEK2	NM_001005735.3		c.813-551T>A		intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.777-551T>A		intron	N/A	NP_001425222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.684-551T>A		intron	N/A	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.813-551T>A		intron	N/A	ENSP00000372023.2
	CHEK2	ENST00000402731.6	TSL:1	c.483-551T>A		intron	N/A	ENSP00000384835.2

Frequencies

GnomAD3 genomes AF: 0.0838 AC: 12739 AN: 152036 Hom.: 610 Cov.: 33

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0654

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0935

Gnomad OTH AF: 0.0660

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

GnomAD4 genome AF: 0.0838 AC: 12747 AN: 152154 Hom.: 612 Cov.: 33 AF XY: 0.0867 AC XY: 6447 AN XY: 74378

African (AFR) AF: 0.0598 AC: 2483 AN: 41508

American (AMR) AF: 0.0659 AC: 1007 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.0956 AC: 495 AN: 5178

South Asian (SAS) AF: 0.105 AC: 504 AN: 4822

European-Finnish (FIN) AF: 0.154 AC: 1625 AN: 10572

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0935 AC: 6356 AN: 67996

Other (OTH) AF: 0.0648 AC: 137 AN: 2114

Alfa AF: 0.104 Hom.: 125

Bravo AF: 0.0730

Asia WGS AF: 0.0900 AC: 314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.73
PromoterAI		-0.086	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9620817; hg19: chr22-29108556;