rs6519761

Variant names:

• chr22-28705612-A-G
• rs6519761
• NM_007194.4:c.847-2046T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007194.4(CHEK2):​c.847-2046T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,044 control chromosomes in the GnomAD database, including 3,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3057 hom., cov: 31)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340
• Publications: 3 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.847-2046T>C		intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.976-2046T>C		intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.940-2046T>C		intron	N/A	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.847-2046T>C		intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.976-2046T>C		intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.646-2046T>C		intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29121 AN: 151926 Hom.: 3048 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.192 AC: 29170 AN: 152044 Hom.: 3057 Cov.: 31 AF XY: 0.197 AC XY: 14620 AN XY: 74324

African (AFR) AF: 0.205 AC: 8495 AN: 41486

American (AMR) AF: 0.275 AC: 4195 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 997 AN: 3470

East Asian (EAS) AF: 0.389 AC: 2004 AN: 5150

South Asian (SAS) AF: 0.266 AC: 1277 AN: 4806

European-Finnish (FIN) AF: 0.133 AC: 1407 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10077 AN: 68004

Other (OTH) AF: 0.226 AC: 475 AN: 2102

Alfa AF: 0.161 Hom.: 959

Bravo AF: 0.206

Asia WGS AF: 0.334 AC: 1160 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.3
DANN	Benign	0.74
PhyloP100		0.34
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: rs6519761; hg19: chr22-29101600; COSMIC: COSV60415644;