Genetic Variant ZCCHC2:p.Lys32Glu (chr18-62523518-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017742.6(ZCCHC2):c.94A>G(p.Lys32Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZCCHC2
NM_017742.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.85

Variant links:

Genes affected

ZCCHC2 (HGNC:22916): (zinc finger CCHC-type containing 2) Predicted to enable nucleic acid binding activity; phosphatidylinositol binding activity; and zinc ion binding activity. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0968793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6 link	c.94A>G	p.Lys32Glu	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4	Q9C0B9-1Q9BRD4
ZCCHC2	NR_126534.2 link	n.494A>G		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZCCHC2	ENST00000269499.10 link	c.94A>G	p.Lys32Glu	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000585873.5 link	n.-150A>G		upstream_gene_variant		1		ENSP00000468789.1	K7ESN2
ZCCHC2	ENST00000588676.1 link	c.-102A>G		upstream_gene_variant		6		ENSP00000465548.1	K7EKB8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

131470

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000267

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000164

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000304

AC:

160

AN:

525964

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

AN XY:

245316

show subpopulations

Gnomad4 AFR exome

AF:

0.000201

Gnomad4 AMR exome

AF:

0.00147

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000910

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000456

AC:

AN:

131504

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

63498

show subpopulations

Gnomad4 AFR

AF:

0.0000812

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000268

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000157

Gnomad4 NFE

AF:

0.0000164

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94A>G (p.K32E) alteration is located in exon 1 (coding exon 1) of the ZCCHC2 gene. This alteration results from a A to G substitution at nucleotide position 94, causing the lysine (K) at amino acid position 32 to be replaced by a glutamic acid (E). 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

0.25

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0045

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.30

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.29

REVEL

Benign

0.037

Sift

Pathogenic

0.0

Sift4G

Benign

0.40

Polyphen

0.13

Vest4

0.11

MutPred

0.20

Loss of MoRF binding (P = 0.0038);

MVP

0.076

MPC

0.053

ClinPred

0.28

GERP RS

0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.11

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