rs2236141

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 24 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]

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]

HSCB Gene-Disease associations (from GenCC):

• anemia, sideroblastic, 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000416671.5. 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.-120G>A		upstream_gene	N/A	NP_009125.1	O96017-1
	HSCB	NM_172002.5	MANE Select	c.-214C>T		upstream_gene	N/A	NP_741999.3
	CHEK2	NM_001005735.3		c.-120G>A		upstream_gene	N/A	NP_001005735.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000416671.5	TSL:1	n.-120G>A		non_coding_transcript_exon	Exon 1 of 16	ENSP00000402225.1	C9JFD7
	CHEK2	ENST00000416671.5	TSL:1	n.-120G>A		5_prime_UTR	Exon 1 of 16	ENSP00000402225.1	C9JFD7
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.-120G>A		upstream_gene	N/A	ENSP00000385747.1	O96017-1

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

African (AFR) AF: 0.0279 AC: 349 AN: 12496

American (AMR) AF: 0.0813 AC: 1504 AN: 18508

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 2344 AN: 13678

East Asian (EAS) AF: 0.202 AC: 6236 AN: 30886

South Asian (SAS) AF: 0.281 AC: 12647 AN: 44980

European-Finnish (FIN) AF: 0.110 AC: 3238 AN: 29310

Middle Eastern (MID) AF: 0.237 AC: 484 AN: 2042

European-Non Finnish (NFE) AF: 0.139 AC: 37836 AN: 272852

Other (OTH) AF: 0.147 AC: 3829 AN: 26030

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

African (AFR) AF: 0.0255 AC: 1059 AN: 41552

American (AMR) AF: 0.0842 AC: 1286 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 584 AN: 3472

East Asian (EAS) AF: 0.191 AC: 987 AN: 5160

South Asian (SAS) AF: 0.291 AC: 1401 AN: 4822

European-Finnish (FIN) AF: 0.103 AC: 1087 AN: 10594

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9409 AN: 68012

Other (OTH) AF: 0.140 AC: 297 AN: 2116

Alfa AF: 0.115 Hom.: 175

Bravo AF: 0.0997

Asia WGS AF: 0.247 AC: 860 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		-1.4
PromoterAI		0.026	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2236141; hg19: chr22-29137870;