chr22-28742109-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_172002.5(HSCB):c.14G>A(p.Arg5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,593,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HSCB
NM_172002.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

Publications

1 publications found

Variant links:

Genes affected

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 links:

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: ClinGen, Ambry Genetics
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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08342913).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172002.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSCB	NM_172002.5	MANE Select	c.14G>A	p.Arg5Lys	missense	Exon 1 of 6	NP_741999.3
HSCB	NM_001318314.2		c.14G>A	p.Arg5Lys	missense	Exon 1 of 5	NP_001305243.1
HSCB	NM_001318315.2		c.14G>A	p.Arg5Lys	missense	Exon 1 of 5	NP_001305244.1	B0QYH2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSCB	ENST00000216027.8	TSL:1 MANE Select	c.14G>A	p.Arg5Lys	missense	Exon 1 of 6	ENSP00000216027.3	Q8IWL3
CHEK2	ENST00000416671.5	TSL:1	n.-347C>T		non_coding_transcript_exon	Exon 1 of 16	ENSP00000402225.1	C9JFD7
CHEK2	ENST00000416671.5	TSL:1	n.-347C>T		5_prime_UTR	Exon 1 of 16	ENSP00000402225.1	C9JFD7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000475

AC:

AN:

210358

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441680

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33126

American (AMR)

AF:

0.00

AC:

AN:

41734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25692

East Asian (EAS)

AF:

0.00

AC:

AN:

38764

South Asian (SAS)

AF:

0.00

AC:

AN:

84936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1102664

Other (OTH)

AF:

0.00

AC:

AN:

59488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.030

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.49

M_CAP

Benign

0.0049

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.4

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.25

REVEL

Benign

0.027

Sift

Benign

0.090

Sift4G

Benign

0.32

Polyphen

0.0020

Vest4

0.28

MutPred

0.49

Loss of methylation at R5 (P = 0.0141)

MVP

0.27

MPC

0.17

ClinPred

0.091

GERP RS

1.9

PromoterAI

-0.041

Neutral

(source)

Varity_R

0.063

gMVP

0.29

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over