rs2236142

Variant names:

• chr22-28741956-G-C
• rs2236142
• ENST00000416671.5:n.-194C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28741956-G-C
• chr22-28741956-G-T

Variant summary

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

The ENST00000416671.5(CHEK2):​n.-194C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 846,056 control chromosomes in the GnomAD database, including 176,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33322 hom., cov: 32)
  • Exomes 𝑓: 0.63 (143301 hom.)
• Consequence: CHEK2 ENST00000416671.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.264
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-28741956-G-C is Benign according to our data. Variant chr22-28741956-G-C is described in ClinVar as Benign. ClinVar VariationId is 1268378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.-194C>G		upstream_gene_variant		ENST00000404276.6	NP_009125.1
HSCB	NM_172002.5	c.-140G>C		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.-194C>G		upstream_gene_variant		1	NM_007194.4	ENSP00000385747.1
HSCB	ENST00000216027.8	c.-140G>C		upstream_gene_variant		1	NM_172002.5	ENSP00000216027.3

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99757 AN: 151974 Hom.: 33304 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.588

GnomAD4 exome AF: 0.633 AC: 439625 AN: 693964 Hom.: 143301 Cov.: 9 AF XY: 0.625 AC XY: 222022 AN XY: 355154

African (AFR) AF: 0.715 AC: 12354 AN: 17270

American (AMR) AF: 0.564 AC: 12728 AN: 22574

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 7737 AN: 15874

East Asian (EAS) AF: 0.355 AC: 11459 AN: 32278

South Asian (SAS) AF: 0.437 AC: 23192 AN: 53068

European-Finnish (FIN) AF: 0.685 AC: 20563 AN: 30026

Middle Eastern (MID) AF: 0.478 AC: 1881 AN: 3934

European-Non Finnish (NFE) AF: 0.678 AC: 328803 AN: 484876

Other (OTH) AF: 0.614 AC: 20908 AN: 34064

GnomAD4 genome AF: 0.656 AC: 99819 AN: 152092 Hom.: 33322 Cov.: 32 AF XY: 0.651 AC XY: 48419 AN XY: 74360

African (AFR) AF: 0.711 AC: 29505 AN: 41488

American (AMR) AF: 0.607 AC: 9275 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1721 AN: 3472

East Asian (EAS) AF: 0.374 AC: 1924 AN: 5150

South Asian (SAS) AF: 0.423 AC: 2041 AN: 4820

European-Finnish (FIN) AF: 0.688 AC: 7274 AN: 10580

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 46056 AN: 67992

Other (OTH) AF: 0.585 AC: 1237 AN: 2114

Alfa AF: 0.680 Hom.: 4425

Bravo AF: 0.650

Asia WGS AF: 0.385 AC: 1339 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

- -

Jun 22, 2018

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	-0.72
CADD	Benign	7.5
DANN	Benign	0.75
PhyloP100		-0.26
PromoterAI		-0.0071	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: rs2236142; hg19: chr22-29137944; COSMIC: COSV53263634;