8-122952160-G-A

Variant names:

• chr8-122952160-G-A
• rs756368144
• NM_014943.5:c.650G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014943.5(ZHX2):​c.650G>A​(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,612,884 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: ZHX2 NM_014943.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 2 publications found

Genes affected

ZHX2 (HGNC:18513): (zinc fingers and homeoboxes 2) The members of the zinc fingers and homeoboxes gene family are nuclear homodimeric transcriptional repressors that interact with the A subunit of nuclear factor-Y (NF-YA) and contain two C2H2-type zinc fingers and five homeobox DNA-binding domains. This gene encodes member 2 of this gene family. In addition to forming homodimers, this protein heterodimerizes with member 1 of the zinc fingers and homeoboxes family. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.11381698).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014943.5. 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
	ZHX2	NM_014943.5	MANE Select	c.650G>A	p.Arg217His	missense	Exon 3 of 4	NP_055758.1	Q9Y6X8
	ZHX2	NM_001362797.2		c.650G>A	p.Arg217His	missense	Exon 4 of 5	NP_001349726.1	Q9Y6X8
	ZHX2	NM_001412796.1		c.650G>A	p.Arg217His	missense	Exon 4 of 5	NP_001399725.1	Q9Y6X8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZHX2	ENST00000314393.6	TSL:1 MANE Select	c.650G>A	p.Arg217His	missense	Exon 3 of 4	ENSP00000314709.4	Q9Y6X8
	ZHX2	ENST00000892386.1		c.650G>A	p.Arg217His	missense	Exon 4 of 5	ENSP00000562445.1
	ZHX2	ENST00000892387.1		c.650G>A	p.Arg217His	missense	Exon 4 of 5	ENSP00000562446.1

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 151080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251252 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727196

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111970

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000530 AC: 8 AN: 151080 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73696

African (AFR) AF: 0.000122 AC: 5 AN: 40970

American (AMR) AF: 0.0000660 AC: 1 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.033
Sift	Benign	0.033	D
Sift4G	Benign	0.13	T
Polyphen		0.033	B
Vest4		0.15
MutPred		0.35		Loss of phosphorylation at T220 (P = 0.077)
MVP		0.39
MPC		0.33
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.35
Mutation Taster		=82/18	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: rs756368144; hg19: chr8-123964400; COSMIC: COSV58715804; COSMIC: COSV58715804;