Genetic Variant NM_001129996.2:c.802C>G (chr19-44032356-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001129996.2(ZNF222):c.802C>G(p.Pro268Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000226 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ZNF222
NM_001129996.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

Publications

2 publications found

Variant links:

Genes affected

ZNF222 (HGNC:13015): (zinc finger protein 222) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF222 links:

ENSG00000267022 (HGNC:):

ENSG00000267022 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061479747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF222	NM_001129996.2 link	c.802C>G	p.Pro268Ala	missense_variant	Exon 4 of 4	ENST00000391960.4	NP_001123468.1	Q9UK12-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF222	ENST00000391960.4 link	c.802C>G	p.Pro268Ala	missense_variant	Exon 4 of 4	1	NM_001129996.2	ENSP00000375822.2	Q9UK12-2
ZNF222	ENST00000187879.12 link	c.682C>G	p.Pro228Ala	missense_variant	Exon 4 of 4	1		ENSP00000187879.6	Q9UK12-1
ENSG00000267022	ENST00000591793.1 link	n.262+4866C>G		intron_variant	Intron 3 of 10	2		ENSP00000467018.1	K7ENM7

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000286

AC:

AN:

251384

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000227

AC:

332

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000254

AC:

283

AN:

1112006

Other (OTH)

AF:

0.000182

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000210

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41516

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.802C>G (p.P268A) alteration is located in exon 4 (coding exon 4) of the ZNF222 gene. This alteration results from a C to G substitution at nucleotide position 802, causing the proline (P) at amino acid position 268 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.

PhyloP100

5.6

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.30

B;.

Vest4

0.31

MVP

0.30

MPC

0.055

ClinPred

0.11

GERP RS

1.7

Varity_R

0.27

gMVP

0.0054

Mutation Taster

=89/11

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

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NM_001129996.2:c.802C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over