12-122473634-T-C

Position:

• chr12-122473634-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017612.5(ZCCHC8):​c.1987A>G​(p.Met663Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00943 in 1,613,976 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (89 hom.)
• Consequence: ZCCHC8 NM_017612.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008665562).
• BP6: Variant 12-122473634-T-C is Benign according to our data. Variant chr12-122473634-T-C is described in ClinVar as [Benign]. Clinvar id is 782302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1067 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC8	NM_017612.5	c.1987A>G	p.Met663Val	missense_variant	14/14	ENST00000633063.3	NP_060082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC8	ENST00000633063.3	c.1987A>G	p.Met663Val	missense_variant	14/14	1	NM_017612.5	ENSP00000488055	P1
ZCCHC8	ENST00000536306.5	c.1273A>G	p.Met425Val	missense_variant	12/12	1		ENSP00000441423
ZCCHC8	ENST00000543897.5	c.1273A>G	p.Met425Val	missense_variant	12/12	1		ENSP00000438993
ZCCHC8	ENST00000538116.5	n.1088A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1067 AN: 152150 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00802 AC: 2000 AN: 249270 Hom.: 18 AF XY: 0.00820 AC XY: 1109 AN XY: 135228

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.00900

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00975

GnomAD4 exome AF: 0.00969 AC: 14158 AN: 1461708 Hom.: 89 Cov.: 31 AF XY: 0.00964 AC XY: 7009 AN XY: 727136

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00681

Gnomad4 FIN exome AF: 0.00846

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.00701 AC: 1067 AN: 152268 Hom.: 7 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74450

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00613

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0101 Hom.: 13

Bravo AF: 0.00654

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.0105 AC: 86

ExAC AF: 0.00853 AC: 1031

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00859

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ZCCHC8: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;T;T
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	.;.;L
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.46	T;T;T
Polyphen		0.99	.;.;D
Vest4		0.56
MVP		0.37
ClinPred		0.019	T
GERP RS		5.7
Varity_R		0.59
gMVP		0.33

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

Other links and lift over

dbSNP: rs139379402; hg19: chr12-122958181;