Genetic Variant ZNF292:p.Cys13Cys (chr6-87155630-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_015021.3(ZNF292):c.39C>T(p.Cys13Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF292
NM_015021.3 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.822

Publications

0 publications found

Variant links:

Genes affected

ZNF292 (HGNC:18410): (zinc finger protein 292) This gene encodes a growth hormone-dependent, zinc finger transcription factor that functions as a tumor suppressor. Naturally occurring mutations in this gene are associated with gastric cancer, colorectal cancer, and chronic lymphocytic leukemia. [provided by RefSeq, May 2017]

ZNF292 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
intellectual developmental disorder, autosomal dominant 64
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ZNF292 links:

ENSG00000272008 (HGNC:):

ENSG00000272008 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.21827966).

BP6

Variant 6-87155630-C-T is Benign according to our data. Variant chr6-87155630-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3055234.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.822 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF292	NM_015021.3 link	c.39C>T	p.Cys13Cys	synonymous_variant	Exon 1 of 8	ENST00000369577.8	NP_055836.1	O60281-1
ZNF292	NM_001351444.2 link	c.-527C>T		5_prime_UTR_variant	Exon 1 of 9		NP_001338373.1
ZNF292	XM_047418459.1 link	c.-695C>T		5_prime_UTR_variant	Exon 1 of 10		XP_047274415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF292	ENST00000369577.8 link	c.39C>T	p.Cys13Cys	synonymous_variant	Exon 1 of 8	1	NM_015021.3	ENSP00000358590.3		O60281-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1429352

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707784

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000304

AC:

AN:

32938

American (AMR)

AF:

0.00

AC:

AN:

39276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25500

East Asian (EAS)

AF:

0.00

AC:

AN:

38144

South Asian (SAS)

AF:

0.00

AC:

AN:

81738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4978

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097244

Other (OTH)

AF:

0.00

AC:

AN:

59164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ZNF292-related disorder

Benign:1

Apr 04, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.038

Eigen

Benign

0.10

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.42

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.61

PhyloP100

0.82

PROVEAN

Benign

-2.3

REVEL

Benign

0.12

Sift

Pathogenic

0.0

MutPred

0.27

Loss of methylation at R4 (P = 0.0189);

MVP

0.39

ClinPred

0.73

GERP RS

3.1

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=92/8

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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6-87155630-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over