19-44027040-G-T

Variant names:

• chr19-44027040-G-T
• rs752974530
• NM_001129996.2:c.60G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001129996.2(ZNF222):​c.60G>T​(p.Lys20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF222 NM_001129996.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.617
• Publications: 0 publications found

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]

ENSG00000267022 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33303428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF222	NM_001129996.2	c.60G>T	p.Lys20Asn	missense_variant	Exon 2 of 4	ENST00000391960.4	NP_001123468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF222	ENST00000391960.4	c.60G>T	p.Lys20Asn	missense_variant	Exon 2 of 4	1	NM_001129996.2	ENSP00000375822.2
ENSG00000267022	ENST00000591793.1	n.60G>T		non_coding_transcript_exon_variant	Exon 2 of 11	2		ENSP00000467018.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.60G>T (p.K20N) alteration is located in exon 2 (coding exon 2) of the ZNF222 gene. This alteration results from a G to T substitution at nucleotide position 60, causing the lysine (K) at amino acid position 20 to be replaced by an asparagine (N). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0059	.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.17	T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M;.
PhyloP100		0.62
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Benign	0.049
Sift	Uncertain	0.027	.;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.25
MutPred		0.50		.;Loss of methylation at K11 (P = 8e-04);.;
MVP		0.40
MPC		0.34
ClinPred		0.94	D
GERP RS		0.54
Varity_R		0.28
gMVP		0.078
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752974530; hg19: chr19-44531192;