chr12-122473630-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017612.5(ZCCHC8):c.1991G>A(p.Ser664Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZCCHC8
NM_017612.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.06

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC8	NM_017612.5 link	c.1991G>A	p.Ser664Asn	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.1991G>A	p.Ser664Asn	missense_variant	Exon 14 of 14	1	NM_017612.5	ENSP00000488055.1	Q6NZY4-1
ZCCHC8	ENST00000536306.5 link	c.1277G>A	p.Ser426Asn	missense_variant	Exon 12 of 12	1		ENSP00000441423.1	Q6NZY4-2
ZCCHC8	ENST00000543897.5 link	c.1277G>A	p.Ser426Asn	missense_variant	Exon 12 of 12	1		ENSP00000438993.1	Q6NZY4-2
ZCCHC8	ENST00000538116.5 link	n.1092G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249266

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

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:

0.00000137

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:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 664 of the ZCCHC8 protein (p.Ser664Asn). This variant is present in population databases (rs770606298, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ZCCHC8-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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

0.48

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

.;.;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Uncertain

-0.029

MutationAssessor

Benign

1.9

.;.;L

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

N;N;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0080

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.68

MutPred

0.42

.;.;Loss of ubiquitination at K665 (P = 0.0505);

MVP

0.68

ClinPred

0.68

GERP RS

5.9

Varity_R

0.72

gMVP

0.67

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