Genetic Variant ZCCHC2:p.Ser35Pro (chr18-62523527-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017742.6(ZCCHC2):c.103T>C(p.Ser35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S35A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000081 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00033 ( 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: 0.895

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047338814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6 link	c.103T>C	p.Ser35Pro	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4	Q9C0B9-1Q9BRD4
ZCCHC2	NR_126534.2 link	n.503T>C		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.103T>C	p.Ser35Pro	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4	Q9C0B9-1
ZCCHC2	ENST00000585873.5 link	n.-141T>C		upstream_gene_variant		1		ENSP00000468789.1	K7ESN2
ZCCHC2	ENST00000588676.1 link	c.-93T>C		upstream_gene_variant		6		ENSP00000465548.1	K7EKB8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

123562

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000319

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:

0.000328

AC:

179

AN:

545014

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

AN XY:

252952

show subpopulations

Gnomad4 AFR exome

AF:

0.000290

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000277

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000809

AC:

AN:

123602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

59524

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000319

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

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

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103T>C (p.S35P) alteration is located in exon 1 (coding exon 1) of the ZCCHC2 gene. This alteration results from a T to C substitution at nucleotide position 103, causing the serine (S) at amino acid position 35 to be replaced by a proline (P). 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

0.044

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.0026

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.15

M_CAP

Benign

0.044

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.51

REVEL

Benign

0.027

Sift

Benign

0.28

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.052

MutPred

0.21

Loss of phosphorylation at S35 (P = 6e-04);

MVP

0.040

MPC

0.049

ClinPred

0.071

GERP RS

1.1

Varity_R

0.090

gMVP

0.092

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over