Variant 12-122473548-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017612.5(ZCCHC8):c.2073G>A(p.Leu691=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,613,946 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 140 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 135 hom. )

Consequence

ZCCHC8
NM_017612.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.28

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 12-122473548-C-T is Benign according to our data. Variant chr12-122473548-C-T is described in ClinVar as [Benign]. Clinvar id is 784476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC8	NM_017612.5 linkuse as main transcript	c.2073G>A	p.Leu691=	synonymous_variant	14/14	ENST00000633063.3	NP_060082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC8	ENST00000633063.3 linkuse as main transcript	c.2073G>A	p.Leu691=	synonymous_variant	14/14	1	NM_017612.5	ENSP00000488055	P1	Q6NZY4-1
ZCCHC8	ENST00000536306.5 linkuse as main transcript	c.1359G>A	p.Leu453=	synonymous_variant	12/12	1		ENSP00000441423		Q6NZY4-2
ZCCHC8	ENST00000543897.5 linkuse as main transcript	c.1359G>A	p.Leu453=	synonymous_variant	12/12	1		ENSP00000438993		Q6NZY4-2
ZCCHC8	ENST00000538116.5 linkuse as main transcript	n.1174G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3849

AN:

152132

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00788

AC:

1965

AN:

249216

Hom.:

AF XY:

0.00638

AC XY:

862

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.0900

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000752

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00330

AC:

4824

AN:

1461696

Hom.:

135

Cov.:

AF XY:

0.00291

AC XY:

2119

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0888

Gnomad4 AMR exome

AF:

0.00619

Gnomad4 ASJ exome

AF:

0.0280

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000314

Gnomad4 OTH exome

AF:

0.00760

GnomAD4 genome

AF:

0.0253

AC:

3856

AN:

152250

Hom.:

140

Cov.:

AF XY:

0.0248

AC XY:

1844

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0845

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.0280

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.00688

Hom.:

Bravo

AF:

0.0290

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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