12-122473511-T-G

Position:

• chr12-122473511-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017612.5(ZCCHC8):​c.2110A>C​(p.Lys704Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: ZCCHC8 NM_017612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14936242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC8	NM_017612.5	c.2110A>C	p.Lys704Gln	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.2110A>C	p.Lys704Gln	missense_variant	14/14	1	NM_017612.5	ENSP00000488055	P1
ZCCHC8	ENST00000536306.5	c.1396A>C	p.Lys466Gln	missense_variant	12/12	1		ENSP00000441423
ZCCHC8	ENST00000543897.5	c.1396A>C	p.Lys466Gln	missense_variant	12/12	1		ENSP00000438993
ZCCHC8	ENST00000538116.5	n.1211A>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.2110A>C (p.K704Q) alteration is located in exon 14 (coding exon 14) of the ZCCHC8 gene. This alteration results from a A to C substitution at nucleotide position 2110, causing the lysine (K) at amino acid position 704 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	.;.;T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.053
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	.;.;L
MutationTaster	Benign	0.77	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.85	N;N;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.59	.;.;P
Vest4		0.35
MutPred		0.33		.;.;Loss of methylation at K704 (P = 0.0111);
MVP		0.42
ClinPred		0.85	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122958058;