chr8-122952156-G-A

Variant names:

• chr8-122952156-G-A
• rs767930305
• NM_014943.5:c.646G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014943.5(ZHX2):​c.646G>A​(p.Ala216Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,226 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ZHX2 NM_014943.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062251538).

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.646G>A	p.Ala216Thr	missense	Exon 3 of 4	NP_055758.1	Q9Y6X8
	ZHX2	NM_001362797.2		c.646G>A	p.Ala216Thr	missense	Exon 4 of 5	NP_001349726.1	Q9Y6X8
	ZHX2	NM_001412796.1		c.646G>A	p.Ala216Thr	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.646G>A	p.Ala216Thr	missense	Exon 3 of 4	ENSP00000314709.4	Q9Y6X8
	ZHX2	ENST00000892386.1		c.646G>A	p.Ala216Thr	missense	Exon 4 of 5	ENSP00000562445.1
	ZHX2	ENST00000892387.1		c.646G>A	p.Ala216Thr	missense	Exon 4 of 5	ENSP00000562446.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151416 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251222 AF XY: 0.0000221

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: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

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

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151416 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73894

African (AFR) AF: 0.00 AC: 0 AN: 41104

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.064
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.035
Sift	Benign	0.62	T
Sift4G	Benign	0.60	T
Polyphen		0.0080	B
Vest4		0.054
MutPred		0.24		Gain of glycosylation at A216 (P = 0.0123)
MVP		0.19
MPC		0.26
ClinPred		0.12	T
GERP RS		3.7
Varity_R		0.063
gMVP		0.33
Mutation Taster		=95/5	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: rs767930305; hg19: chr8-123964396;