rs774192195

Variant names:

• chr22-28734610-T-C
• rs774192195
• NM_007194.4:c.112A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28734610-T-C
• chr22-28734610-T-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_007194.4(CHEK2):​c.112A>G​(p.Ile38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I38T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0170
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02486518).
• BP6: Variant 22-28734610-T-C is Benign according to our data. Variant chr22-28734610-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 583047.

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.112A>G	p.Ile38Val	missense	Exon 2 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.112A>G	p.Ile38Val	missense	Exon 2 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.112A>G	p.Ile38Val	missense	Exon 2 of 16	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.112A>G	p.Ile38Val	missense	Exon 2 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.112A>G	p.Ile38Val	missense	Exon 2 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.112A>G	p.Ile38Val	missense	Exon 1 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250756 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.0
DANN	Benign	0.26
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.017
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.033
Sift	Benign	0.51	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.24		Gain of catalytic residue at I38 (P = 0.0544)
MVP		0.39
MPC		0.019
ClinPred		0.023	T
GERP RS		-2.7
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.069
Mutation Taster		=97/3	polymorphism

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: rs774192195; hg19: chr22-29130598;