dbSNP rs1805129: CHEK2:p.Glu84Glu (chr22-28734470-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007194.4(CHEK2):c.252A>G(p.Glu84Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,612,750 control chromosomes in the GnomAD database, including 1,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 164 hom., cov: 31)

Exomes 𝑓: 0.029 ( 865 hom. )

Consequence

CHEK2
NM_007194.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.284

Publications

25 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, ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
hereditary breast carcinoma
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: Unknown 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 22-28734470-T-C is Benign according to our data. Variant chr22-28734470-T-C is described in ClinVar as Benign. ClinVar VariationId is 142139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.284 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0718 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHEK2	NM_007194.4	MANE Select	c.252A>G	p.Glu84Glu	synonymous	Exon 2 of 15	NP_009125.1	O96017-1
CHEK2	NM_001005735.3		c.252A>G	p.Glu84Glu	synonymous	Exon 2 of 16	NP_001005735.1
CHEK2	NM_001438293.1		c.252A>G	p.Glu84Glu	synonymous	Exon 2 of 16	NP_001425222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.252A>G	p.Glu84Glu	synonymous	Exon 2 of 15	ENSP00000385747.1	O96017-1
CHEK2	ENST00000382580.6	TSL:1	c.252A>G	p.Glu84Glu	synonymous	Exon 2 of 16	ENSP00000372023.2	O96017-9
CHEK2	ENST00000402731.6	TSL:1	c.252A>G	p.Glu84Glu	synonymous	Exon 1 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5939

AN:

151196

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0646

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0892

Gnomad EAS

AF:

0.0789

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.0255

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.0355

AC:

8931

AN:

251438

AF XY:

0.0351

show subpopulations

Gnomad AFR exome

AF:

0.0666

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0852

Gnomad EAS exome

AF:

0.0898

Gnomad FIN exome

AF:

0.0289

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0289

AC:

42275

AN:

1461438

Hom.:

865

Cov.:

AF XY:

0.0294

AC XY:

21358

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0693

AC:

2321

AN:

33474

American (AMR)

AF:

0.0127

AC:

569

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0842

AC:

2198

AN:

26110

East Asian (EAS)

AF:

0.0527

AC:

2090

AN:

39688

South Asian (SAS)

AF:

0.0383

AC:

3300

AN:

86212

European-Finnish (FIN)

AF:

0.0272

AC:

1455

AN:

53396

Middle Eastern (MID)

AF:

0.0427

AC:

246

AN:

5764

European-Non Finnish (NFE)

AF:

0.0250

AC:

27756

AN:

1111706

Other (OTH)

AF:

0.0388

AC:

2340

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

2197

4395

6592

8790

10987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1158

2316

3474

4632

5790

<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:

0.0393

AC:

5949

AN:

151312

Hom.:

164

Cov.:

AF XY:

0.0392

AC XY:

2895

AN XY:

73922

show subpopulations

African (AFR)

AF:

0.0649

AC:

2673

AN:

41214

American (AMR)

AF:

0.0213

AC:

324

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.0892

AC:

309

AN:

3464

East Asian (EAS)

AF:

0.0781

AC:

400

AN:

5120

South Asian (SAS)

AF:

0.0350

AC:

167

AN:

4768

European-Finnish (FIN)

AF:

0.0255

AC:

268

AN:

10518

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1724

AN:

67736

Other (OTH)

AF:

0.0312

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

286

572

859

1145

1431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0307

Hom.:

171

Bravo

AF:

0.0403

EpiCase

AF:

0.0254

EpiControl

AF:

0.0251

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Familial cancer of breast (4)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

CHEK2-related cancer predisposition (2)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.4

(source)

DANN

Benign

0.70

PhyloP100

0.28

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=300/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over