Genetic Variant ZCCHC2:p.Arg65Gln (chr18-62523618-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017742.6(ZCCHC2):c.194G>A(p.Arg65Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 145,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000029 ( 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: -1.18

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11989376).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017742.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC2	NM_017742.6	MANE Select	c.194G>A	p.Arg65Gln	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.594G>A		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZCCHC2	ENST00000269499.10	TSL:5 MANE Select	c.194G>A	p.Arg65Gln	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000963441.1		c.194G>A	p.Arg65Gln	missense	Exon 1 of 14	ENSP00000633500.1
ZCCHC2	ENST00000585873.5	TSL:1	n.-50G>A		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes

AF:

0.00000687

AC:

AN:

145658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000288

AC:

AN:

1040326

Hom.:

Cov.:

AF XY:

0.00000611

AC XY:

AN XY:

490912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21398

American (AMR)

AF:

0.00

AC:

AN:

6940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12544

East Asian (EAS)

AF:

0.00

AC:

AN:

23282

South Asian (SAS)

AF:

0.00

AC:

AN:

19012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2708

European-Non Finnish (NFE)

AF:

0.00000335

AC:

AN:

894662

Other (OTH)

AF:

0.00

AC:

AN:

40622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000687

AC:

AN:

145658

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70762

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40478

American (AMR)

AF:

0.00

AC:

AN:

14698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4808

South Asian (SAS)

AF:

0.00

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65758

Other (OTH)

AF:

0.00

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.43

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-1.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.33

REVEL

Benign

0.035

Sift

Benign

0.083

Sift4G

Benign

0.32

Polyphen

0.90

Vest4

0.15

MutPred

0.24

Loss of methylation at R65 (P = 0.0098)

MVP

0.030

MPC

0.046

ClinPred

0.24

GERP RS

1.7

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.046

gMVP

0.12

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over