12-122473531-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017612.5(ZCCHC8):c.2090G>A(p.Arg697Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ZCCHC8
NM_017612.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.08

Variant links:

Genes affected

ZCCHC8 (HGNC:25265): (zinc finger CCHC-type containing 8) This gene encodes a scaffold protein which serves as an assessory factor to the nuclear RNA exosome complex. The encoded protein forms a trimeric human nuclear exosome targeting (NEXT) complex, together with hMTR4 and the RNA-binding factor RBM7 which promotes the exosomal degradation of non-coding promoter-upstream transcripts, enhancer RNAs and 3'-extended products of histone- and small nuclear RNA transcription. This complex is also thought to recruit the exosome to degrade intronic RNAs via its interaction with both the exosome and the spliceosome. It contains both an N-terminal zinc-knuckle domain and a C-terminal proline-rich domain. [provided by RefSeq, Apr 2017]

ZCCHC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC8	NM_017612.5 link	c.2090G>A	p.Arg697Gln	missense_variant	Exon 14 of 14	ENST00000633063.3	NP_060082.2	Q6NZY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZCCHC8	ENST00000633063.3 link	c.2090G>A	p.Arg697Gln	missense_variant	Exon 14 of 14	1	NM_017612.5	ENSP00000488055.1	Q6NZY4-1
ZCCHC8	ENST00000536306.5 link	c.1376G>A	p.Arg459Gln	missense_variant	Exon 12 of 12	1		ENSP00000441423.1	Q6NZY4-2
ZCCHC8	ENST00000543897.5 link	c.1376G>A	p.Arg459Gln	missense_variant	Exon 12 of 12	1		ENSP00000438993.1	Q6NZY4-2
ZCCHC8	ENST00000538116.5 link	n.1191G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249130

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2090G>A (p.R697Q) alteration is located in exon 14 (coding exon 14) of the ZCCHC8 gene. This alteration results from a G to A substitution at nucleotide position 2090, causing the arginine (R) at amino acid position 697 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 697 of the ZCCHC8 protein (p.Arg697Gln). This variant is present in population databases (rs374767090, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ZCCHC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 2604930). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ZCCHC8 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

.;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.9

.;.;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;N;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.56

MVP

0.69

ClinPred

0.96

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.56

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