rs1300388084

Positions:

• chr22-28699839-T-A
• chr22-28699839-T-C
• chr22-28699839-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007194.4(CHEK2):​c.1007A>T​(p.Gln336Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1007A>T	p.Gln336Leu	missense_variant, splice_region_variant	9/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1007A>T	p.Gln336Leu	missense_variant, splice_region_variant	9/15	1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	.;T;.;D;.;D;D;D;.;D;T;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.58	N;N;N;.;N;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.026	D;D;D;.;D;T;.;D;D;D;.;D
Sift4G	Uncertain	0.031	D;D;D;.;D;D;.;T;D;T;.;.
Polyphen		0.69	P;P;P;.;P;P;P;D;P;.;.;.
Vest4		0.58
MutPred		0.54		Loss of catalytic residue at Q336 (P = 0.054);Loss of catalytic residue at Q336 (P = 0.054);Loss of catalytic residue at Q336 (P = 0.054);.;Loss of catalytic residue at Q336 (P = 0.054);.;Loss of catalytic residue at Q336 (P = 0.054);.;Loss of catalytic residue at Q336 (P = 0.054);.;.;.;
MVP		0.90
MPC		0.069
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29095827;