rs1033667

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007194.4(CHEK2):c.319+91G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,259,652 control chromosomes in the GnomAD database, including 50,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6926 hom., cov: 32)

Exomes 𝑓: 0.27 ( 43541 hom. )

Consequence

CHEK2
NM_007194.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.497

Publications

26 publications found

Variant links:

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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 22-28734312-C-T is Benign according to our data. Variant chr22-28734312-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.319+91G>A		intron_variant	Intron 2 of 14	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.319+91G>A		intron_variant	Intron 2 of 14	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44765

AN:

151910

Hom.:

6910

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.279

GnomAD4 exome

AF:

0.275

AC:

304485

AN:

1107624

Hom.:

43541

AF XY:

0.270

AC XY:

151736

AN XY:

561960

show subpopulations

African (AFR)

AF:

0.345

AC:

8799

AN:

25486

American (AMR)

AF:

0.319

AC:

11056

AN:

34630

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

3938

AN:

22860

East Asian (EAS)

AF:

0.200

AC:

7273

AN:

36364

South Asian (SAS)

AF:

0.174

AC:

12767

AN:

73450

European-Finnish (FIN)

AF:

0.253

AC:

12923

AN:

50992

Middle Eastern (MID)

AF:

0.184

AC:

895

AN:

4872

European-Non Finnish (NFE)

AF:

0.288

AC:

233679

AN:

810746

Other (OTH)

AF:

0.273

AC:

13155

AN:

48224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

11168

22335

33503

44670

55838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6838

13676

20514

27352

34190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.295

AC:

44817

AN:

152028

Hom.:

6926

Cov.:

AF XY:

0.292

AC XY:

21681

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.346

AC:

14337

AN:

41474

American (AMR)

AF:

0.339

AC:

5173

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

615

AN:

3472

East Asian (EAS)

AF:

0.214

AC:

1104

AN:

5166

South Asian (SAS)

AF:

0.160

AC:

770

AN:

4826

European-Finnish (FIN)

AF:

0.266

AC:

2811

AN:

10548

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19074

AN:

67964

Other (OTH)

AF:

0.284

AC:

598

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1632

3263

4895

6526

8158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.282

Hom.:

16188

Bravo

AF:

0.304

Asia WGS

AF:

0.190

AC:

658

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.4

(source)

DANN

Benign

0.34

PhyloP100

-0.50

PromoterAI

-0.0056

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over