22-28687820-TA-T

Variant names:

• chr22-28687820-TA-T
• rs541513166
• ENST00000416671.5:n.*1198delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_007194.4(CHEK2):​c.*76delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.*76delT		3_prime_UTR_variant	Exon 15 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.*76delT		3_prime_UTR_variant	Exon 15 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 240 AN: 143536 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00116

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000905

Gnomad EAS AF: 0.00143

Gnomad SAS AF: 0.00408

Gnomad FIN AF: 0.00392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00363

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000108 AC: 11 AN: 1018114 Hom.: 0 Cov.: 13 AF XY: 0.0000134 AC XY: 7 AN XY: 521942

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000400 AC: 1 AN: 24986

American (AMR) AF: 0.00 AC: 0 AN: 38894

Ashkenazi Jewish (ASJ) AF: 0.0000868 AC: 2 AN: 23036

East Asian (EAS) AF: 0.00 AC: 0 AN: 36528

South Asian (SAS) AF: 0.00 AC: 0 AN: 73976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00000952 AC: 7 AN: 735608

Other (OTH) AF: 0.0000218 AC: 1 AN: 45828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00167 AC: 240 AN: 143654 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 142 AN XY: 69848

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00101 AC: 40 AN: 39424

American (AMR) AF: 0.00209 AC: 30 AN: 14386

Ashkenazi Jewish (ASJ) AF: 0.000905 AC: 3 AN: 3314

East Asian (EAS) AF: 0.00144 AC: 7 AN: 4876

South Asian (SAS) AF: 0.00408 AC: 18 AN: 4412

European-Finnish (FIN) AF: 0.00392 AC: 38 AN: 9706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00149 AC: 96 AN: 64428

Other (OTH) AF: 0.00359 AC: 7 AN: 1952

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000273 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

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: rs541513166; hg19: chr22-29083808;