18-62523594-C-G

Variant names:

• chr18-62523594-C-G
• rs927746382
• NM_017742.6:c.170C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017742.6(ZCCHC2):​c.170C>G​(p.Pro57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,027,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P57L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.211
• Publications: 0 publications found

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

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=0.11807957).

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.170C>G	p.Pro57Arg	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.570C>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC2	ENST00000269499.10	TSL:5 MANE Select	c.170C>G	p.Pro57Arg	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
	ZCCHC2	ENST00000963441.1		c.170C>G	p.Pro57Arg	missense	Exon 1 of 14	ENSP00000633500.1
	ZCCHC2	ENST00000585873.5	TSL:1	n.-74C>G		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 2 AN: 142254 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000311

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000791 AC: 7 AN: 885426 Hom.: 0 Cov.: 57 AF XY: 0.00000968 AC XY: 4 AN XY: 413356

African (AFR) AF: 0.00 AC: 0 AN: 17228

American (AMR) AF: 0.00 AC: 0 AN: 2984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7308

East Asian (EAS) AF: 0.00 AC: 0 AN: 9484

South Asian (SAS) AF: 0.00 AC: 0 AN: 16974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2006

European-Non Finnish (NFE) AF: 0.00000884 AC: 7 AN: 792106

Other (OTH) AF: 0.00 AC: 0 AN: 30928

GnomAD4 genome AF: 0.0000141 AC: 2 AN: 142254 Hom.: 0 Cov.: 31 AF XY: 0.0000145 AC XY: 1 AN XY: 69066

African (AFR) AF: 0.00 AC: 0 AN: 39728

American (AMR) AF: 0.00 AC: 0 AN: 14464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3360

East Asian (EAS) AF: 0.00 AC: 0 AN: 4632

South Asian (SAS) AF: 0.00 AC: 0 AN: 4540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000311 AC: 2 AN: 64354

Other (OTH) AF: 0.00 AC: 0 AN: 1970

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.0
DANN	Benign	0.91
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.21
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.055
Sift	Benign	0.070	T
Sift4G	Uncertain	0.033	D
Polyphen		0.95	P
Vest4		0.11
MutPred		0.23		Gain of methylation at P57 (P = 0.0071)
MVP		0.072
MPC		0.044
ClinPred		0.16	T
GERP RS		2.1
PromoterAI		-0.074	Neutral
Varity_R		0.033
gMVP		0.23
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs927746382; hg19: chr18-60190827;