Variant 19-43966125-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000587682.6(ZNF221):c.623G>C(p.Cys208Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. C208Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ZNF221
ENST00000587682.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.22

Variant links:

Genes affected

ZNF221 (HGNC:13014): (zinc finger protein 221) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF221 links:

ZNF221 (HGNC:):

ZNF221 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0284383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF221	NM_001297588.2 linkuse as main transcript	c.623G>C	p.Cys208Ser	missense_variant	5/5	ENST00000587682.6	NP_001284517.1	Q9UK13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF221	ENST00000587682.6 linkuse as main transcript	c.623G>C	p.Cys208Ser	missense_variant	5/5	1	NM_001297588.2	ENSP00000467367.1	Q9UK13
ZNF221	ENST00000251269.9 linkuse as main transcript	c.623G>C	p.Cys208Ser	missense_variant	6/6	1		ENSP00000251269.4	Q9UK13
ZNF221	ENST00000592350.5 linkuse as main transcript	c.623G>C	p.Cys208Ser	missense_variant	6/6	1		ENSP00000467446.1	Q9UK13
ZNF221	ENST00000622072.1 linkuse as main transcript	c.623G>C	p.Cys208Ser	missense_variant	4/4	2		ENSP00000477876.1	Q9UK13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251354

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000564

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.623G>C (p.C208S) alteration is located in exon 6 (coding exon 4) of the ZNF221 gene. This alteration results from a G to C substitution at nucleotide position 623, causing the cysteine (C) at amino acid position 208 to be replaced by a serine (S). 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

0.25

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.17

DANN

Benign

0.51

DEOGEN2

Benign

0.016

T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.42

.;.;.;T

M_CAP

Benign

0.00082

MetaRNN

Benign

0.028

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.95

N;N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.4

.;N;.;.

REVEL

Benign

0.025

Sift

Benign

0.98

.;T;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.22

B;B;B;B

Vest4

0.049

MutPred

0.40

Gain of disorder (P = 0.0121);Gain of disorder (P = 0.0121);Gain of disorder (P = 0.0121);Gain of disorder (P = 0.0121);

MVP

0.076

MPC

0.028

ClinPred

0.066

GERP RS

1.5

Varity_R

0.069

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over