Variant 12-122473627-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000633063.3(ZCCHC8):c.1994A>G(p.Lys665Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ZCCHC8
ENST00000633063.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79

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:

ZCCHC8 (HGNC:):

ZCCHC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22697821).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC8	NM_017612.5 linkuse as main transcript	c.1994A>G	p.Lys665Arg	missense_variant	14/14	ENST00000633063.3	NP_060082.2	Q6NZY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZCCHC8	ENST00000633063.3 linkuse as main transcript	c.1994A>G	p.Lys665Arg	missense_variant	14/14	1	NM_017612.5	ENSP00000488055.1	Q6NZY4-1
ZCCHC8	ENST00000536306.5 linkuse as main transcript	c.1280A>G	p.Lys427Arg	missense_variant	12/12	1		ENSP00000441423.1	Q6NZY4-2
ZCCHC8	ENST00000543897.5 linkuse as main transcript	c.1280A>G	p.Lys427Arg	missense_variant	12/12	1		ENSP00000438993.1	Q6NZY4-2
ZCCHC8	ENST00000538116.5 linkuse as main transcript	n.1095A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249272

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZCCHC8-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2023

The ZCCHC8 c.1994A>G variant is predicted to result in the amino acid substitution p.Lys665Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-122958174-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

.;.;T

Eigen

Benign

-0.086

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

.;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

.;.;L

MutationTaster

Benign

0.87

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.5

N;N;.

REVEL

Benign

0.10

Sift

Benign

0.16

T;T;.

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0070

.;.;B

Vest4

0.23

MutPred

0.46

.;.;Loss of methylation at K665 (P = 0.0118);

MVP

0.20

ClinPred

0.39

GERP RS

4.8

Varity_R

0.22

gMVP

0.34

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