18-62523497-G-T

Variant names:

• chr18-62523497-G-T
• rs749046042
• NM_017742.6:c.73G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 12/20 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.152

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6	c.73G>T	p.Ala25Ser	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4
ZCCHC2	NR_126534.2	n.473G>T		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZCCHC2	ENST00000269499.10	c.73G>T	p.Ala25Ser	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4
ZCCHC2	ENST00000585873.5	n.-171G>T		upstream_gene_variant		1		ENSP00000468789.1
ZCCHC2	ENST00000588676.1	c.-123G>T		upstream_gene_variant		6		ENSP00000465548.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1679 AN: 144752 Hom.: 39 Cov.: 28

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

GnomAD3 exomes AF: 0.00156 AC: 15 AN: 9638 Hom.: 0 AF XY: 0.00121 AC XY: 8 AN XY: 6614

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 SAS 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.: 18 Cov.: 36 AF XY: 0.000805 AC XY: 322 AN XY: 400108

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.000930

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000446

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000104

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.0116 AC: 1683 AN: 144796 Hom.: 39 Cov.: 28 AF XY: 0.0112 AC XY: 787 AN XY: 70406

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.00402

Gnomad4 ASJ AF: 0.000889

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000766

Gnomad4 OTH AF: 0.00545

Alfa AF: 0.00804 Hom.: 0

ExAC AF: 0.000917 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 12, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Polyphen		0.015	B
Vest4		0.092
MVP		0.12
MPC		0.040
ClinPred		0.088	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.14

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

Other links and lift over

dbSNP: rs749046042; hg19: chr18-60190730;