22-28742219-T-G

Position:

• chr22-28742219-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_172002.5(HSCB):​c.124T>G​(p.Trp42Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSCB NM_172002.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

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]

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSCB	NM_172002.5	c.124T>G	p.Trp42Gly	missense_variant	1/6	ENST00000216027.8	NP_741999.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSCB	ENST00000216027.8	c.124T>G	p.Trp42Gly	missense_variant	1/6	1	NM_172002.5	ENSP00000216027.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anemia, sideroblastic, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.124T>G (p.Trp42Gly) variant in HSCB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Trp42Gly variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Trp42Gly in HSCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Trp at position 42 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.71	T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.39	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-10	D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.64		Gain of disorder (P = 0.0172);Gain of disorder (P = 0.0172);
MVP		0.84
MPC		0.95
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29138207;