Genetic Variant NM_017742.6:c.73G>T (chr18-62523497-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_017742.6(ZCCHC2):c.73G>T(p.Ala25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 999,716 control chromosomes in the GnomAD database, including 57 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., cov: 28)

Exomes 𝑓: 0.00093 ( 18 hom. )

Consequence

ZCCHC2
NM_017742.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.152

Publications

1 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018891394).

BP6

Variant 18-62523497-G-T is Benign according to our data. Variant chr18-62523497-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2343101.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1683/144796) while in subpopulation AFR AF = 0.0397 (1603/40372). AF 95% confidence interval is 0.0381. There are 39 homozygotes in GnomAd4. There are 787 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AR gene

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.73G>T	p.Ala25Ser	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.473G>T		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.73G>T	p.Ala25Ser	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000963441.1		c.73G>T	p.Ala25Ser	missense	Exon 1 of 14	ENSP00000633500.1
ZCCHC2	ENST00000585873.5	TSL:1	n.-171G>T		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1679

AN:

144752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00402

Gnomad ASJ

AF:

0.000889

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000766

Gnomad OTH

AF:

0.00549

GnomAD2 exomes

AF:

0.00156

AC:

AN:

9638

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00698

Gnomad ASJ exome

AF:

0.00281

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.000932

AC:

797

AN:

854920

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

322

AN XY:

400108

show subpopulations

African (AFR)

AF:

0.0445

AC:

712

AN:

15984

American (AMR)

AF:

0.00338

AC:

AN:

1776

Ashkenazi Jewish (ASJ)

AF:

0.000930

AC:

AN:

6452

East Asian (EAS)

AF:

0.00

AC:

AN:

4042

South Asian (SAS)

AF:

0.0000446

AC:

AN:

22444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1472

Middle Eastern (MID)

AF:

0.00172

AC:

AN:

1746

European-Non Finnish (NFE)

AF:

0.0000104

AC:

AN:

772898

Other (OTH)

AF:

0.00217

AC:

AN:

28106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.0116

AC:

1683

AN:

144796

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

787

AN XY:

70406

show subpopulations

African (AFR)

AF:

0.0397

AC:

1603

AN:

40372

American (AMR)

AF:

0.00402

AC:

AN:

14676

Ashkenazi Jewish (ASJ)

AF:

0.000889

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

4896

South Asian (SAS)

AF:

0.000421

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000766

AC:

AN:

65252

Other (OTH)

AF:

0.00545

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00804

Hom.:

ExAC

AF:

0.000917

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

Benign

0.12

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.15

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.010

REVEL

Benign

0.033

Sift

Pathogenic

0.0

Sift4G

Benign

0.22

Polyphen

0.015

Vest4

0.092

MVP

0.12

MPC

0.040

ClinPred

0.088

GERP RS

1.1

PromoterAI

-0.0094

Neutral

(source)

Varity_R

0.11

gMVP

0.14

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over