Genetic Variant ZCCHC2:p.Pro16Leu (chr18-62523471-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017742.6(ZCCHC2):c.47C>T(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,090,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000069 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ZCCHC2
NM_017742.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.259

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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06298244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6 link	c.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4	Q9C0B9-1Q9BRD4
ZCCHC2	NR_126534.2 link	n.447C>T		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.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000585873.5 link	n.-197C>T		upstream_gene_variant		1		ENSP00000468789.1	K7ESN2
ZCCHC2	ENST00000588676.1 link	c.-149C>T		upstream_gene_variant		6		ENSP00000465548.1	K7EKB8

Frequencies

GnomAD3 genomes

AF:

0.0000686

AC:

AN:

145842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000137

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

111

AN:

944976

Hom.:

Cov.:

AF XY:

0.0000964

AC XY:

AN XY:

456342

show subpopulations

Gnomad4 AFR exome

AF:

0.0000561

Gnomad4 AMR exome

AF:

0.0000892

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:

0.000130

Gnomad4 OTH exome

AF:

0.0000627

GnomAD4 genome

AF:

0.0000686

AC:

AN:

145842

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

70922

show subpopulations

Gnomad4 AFR

AF:

0.0000246

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000137

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000866

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47C>T (p.P16L) alteration is located in exon 1 (coding exon 1) of the ZCCHC2 gene. This alteration results from a C to T substitution at nucleotide position 47, causing the proline (P) at amino acid position 16 to be replaced by a leucine (L). 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

0.18

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0047

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.42

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.58

REVEL

Benign

0.071

Sift

Benign

0.091

Sift4G

Uncertain

0.014

Polyphen

0.035

Vest4

0.30

MutPred

0.14

Loss of glycosylation at P16 (P = 0.0245);

MVP

0.014

MPC

0.043

ClinPred

0.082

GERP RS

0.97

Varity_R

0.045

gMVP

0.17

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