Genetic Variant ZCCHC2:p.Thr11Ala (chr18-62523455-A-G) – 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.31A>G(p.Thr11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,088,284 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00029 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

ZCCHC2
NM_017742.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.702

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=0.04636833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6 link	c.31A>G	p.Thr11Ala	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4	Q9C0B9-1Q9BRD4
ZCCHC2	NR_126534.2 link	n.431A>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.31A>G	p.Thr11Ala	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000585873.5 link	n.-213A>G		upstream_gene_variant		1		ENSP00000468789.1	K7ESN2
ZCCHC2	ENST00000588676.1 link	c.-165A>G		upstream_gene_variant		6		ENSP00000465548.1	K7EKB8

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

137824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000497

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:

0.000366

Gnomad OTH

AF:

0.000513

GnomAD3 exomes

AF:

0.000101

AC:

AN:

59524

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

35398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000100

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000226

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000244

AC:

232

AN:

950460

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

112

AN XY:

459950

show subpopulations

Gnomad4 AFR exome

AF:

0.0000557

Gnomad4 AMR exome

AF:

0.0000831

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:

0.000266

Gnomad4 OTH exome

AF:

0.000344

GnomAD4 genome

AF:

0.000290

AC:

AN:

137824

Hom.:

Cov.:

AF XY:

0.000225

AC XY:

AN XY:

66672

show subpopulations

Gnomad4 AFR

AF:

0.000230

Gnomad4 AMR

AF:

0.000497

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000366

Gnomad4 OTH

AF:

0.000513

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.000317

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31A>G (p.T11A) 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 31, causing the threonine (T) at amino acid position 11 to be replaced by an alanine (A). 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

0.074

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.0041

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.25

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.52

REVEL

Benign

0.077

Sift

Benign

0.031

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.041

MutPred

0.11

Loss of phosphorylation at T11 (P = 0.0026);

MVP

0.16

MPC

0.042

ClinPred

0.032

GERP RS

2.1

Varity_R

0.086

gMVP

0.28

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