rs2236141

Variant names:

• chr22-28741882-C-T
• rs2236141
• ENST00000416671.5:n.-120G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000416671.5(CHEK2):​n.-120G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 602,986 control chromosomes in the GnomAD database, including 7,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1178 hom., cov: 31)
  • Exomes 𝑓: 0.15 (6116 hom.)
• Consequence: CHEK2 ENST00000416671.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.39

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]

HSCB (HGNC:28913): (HscB mitochondrial iron-sulfur cluster cochaperone) This gene encodes a DnaJ-type co-chaperone and member of the heat shock cognate B (HscB) family of proteins. The encoded protein plays a role in the synthesis of iron-sulfur clusters, protein cofactors that are involved in the redox reactions of mitochondrial electron transport and other processes. Cells in which this gene is knocked down exhibit reduced activity of iron-sulfur cluster-dependent enzymes including succinate dehydrogenase and aconitase. The encoded protein may stimulate the ATPase activity of the mitochondrial stress-70 protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 22-28741882-C-T is Benign according to our data. Variant chr22-28741882-C-T is described in ClinVar as [Benign]. Clinvar id is 1167537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.-120G>A		upstream_gene_variant		ENST00000404276.6	NP_009125.1
HSCB	NM_172002.5	c.-214C>T		upstream_gene_variant		ENST00000216027.8	NP_741999.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.-120G>A		upstream_gene_variant		1	NM_007194.4	ENSP00000385747.1
HSCB	ENST00000216027.8	c.-214C>T		upstream_gene_variant		1	NM_172002.5	ENSP00000216027.3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16260 AN: 152086 Hom.: 1181 Cov.: 31

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.0914

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.152 AC: 68467 AN: 450782 Hom.: 6116 Cov.: 4 AF XY: 0.159 AC XY: 37737 AN XY: 236742

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.0813

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.107 AC: 16258 AN: 152204 Hom.: 1178 Cov.: 31 AF XY: 0.108 AC XY: 8005 AN XY: 74402

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.0842

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.140

Alfa AF: 0.118 Hom.: 175

Bravo AF: 0.0997

Asia WGS AF: 0.247 AC: 860 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20462940) -

Familial cancer of breast Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.33
CADD	Benign	10
DANN	Benign	0.92

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2236141; hg19: chr22-29137870;