22-28725095-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_Very_StrongBP7BS2_Supporting

The NM_007194.4(CHEK2):​c.474A>C​(p.Ala158Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A158A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.188

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 22-28725095-T-G is Benign according to our data. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725095-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 183909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.188 with no splicing effect.
BS2
High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.474A>C p.Ala158Ala synonymous_variant Exon 4 of 15 ENST00000404276.6 NP_009125.1 O96017-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.474A>C p.Ala158Ala synonymous_variant Exon 4 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251416
AF XY:
0.0000589
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000105
AC:
153
AN:
1461818
Hom.:
0
Cov.:
32
AF XY:
0.0000990
AC XY:
72
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000136
AC:
151
AN:
1111974
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
9
18
26
35
44
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.0000460
AC:
7
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.0000942
AC:
1
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000882
AC:
6
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.568
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3
Dec 26, 2014
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 27, 2016
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 26, 2021
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

not specified Benign:2
Apr 26, 2019
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 28, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
Nov 30, 2017
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial cancer of breast Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 02, 2024
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
7.1
DANN
Benign
0.69
PhyloP100
0.19
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs745699485; hg19: chr22-29121083; API