22-28695049-G-C

Variant names:

• chr22-28695049-G-C
• rs5762749
• NM_007194.4:c.1375+78C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007194.4(CHEK2):​c.1375+78C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 860,542 control chromosomes in the GnomAD database, including 178,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28239 hom., cov: 32)
  • Exomes 𝑓: 0.65 (150544 hom.)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.158
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-28695049-G-C is Benign according to our data. Variant chr22-28695049-G-C is described in ClinVar as Benign. ClinVar VariationId is 1254473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1375+78C>G		intron_variant	Intron 12 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1375+78C>G		intron_variant	Intron 12 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92012 AN: 151944 Hom.: 28229 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.649 AC: 459918 AN: 708480 Hom.: 150544 AF XY: 0.655 AC XY: 246694 AN XY: 376848

African (AFR) AF: 0.513 AC: 9757 AN: 19024

American (AMR) AF: 0.632 AC: 24696 AN: 39060

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 14747 AN: 20658

East Asian (EAS) AF: 0.695 AC: 24389 AN: 35106

South Asian (SAS) AF: 0.736 AC: 50116 AN: 68064

European-Finnish (FIN) AF: 0.663 AC: 33182 AN: 50028

Middle Eastern (MID) AF: 0.676 AC: 2740 AN: 4054

European-Non Finnish (NFE) AF: 0.636 AC: 278186 AN: 437644

Other (OTH) AF: 0.634 AC: 22105 AN: 34842

GnomAD4 genome AF: 0.605 AC: 92049 AN: 152062 Hom.: 28239 Cov.: 32 AF XY: 0.606 AC XY: 45042 AN XY: 74300

African (AFR) AF: 0.507 AC: 21048 AN: 41474

American (AMR) AF: 0.583 AC: 8903 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2485 AN: 3472

East Asian (EAS) AF: 0.635 AC: 3278 AN: 5162

South Asian (SAS) AF: 0.749 AC: 3609 AN: 4820

European-Finnish (FIN) AF: 0.650 AC: 6857 AN: 10552

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43710 AN: 67982

Other (OTH) AF: 0.631 AC: 1334 AN: 2114

Alfa AF: 0.628 Hom.: 3755

Bravo AF: 0.596

Asia WGS AF: 0.723 AC: 2516 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.81
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		-0.16
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: rs5762749; hg19: chr22-29091037; COSMIC: COSV60415565; COSMIC: COSV60415565;