18-62523600-C-A

Variant names:

• chr18-62523600-C-A
• rs915021992
• NM_017742.6:c.176C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017742.6(ZCCHC2):​c.176C>A​(p.Pro59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000308 in 975,518 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. P59R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27603436).

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.176C>A	p.Pro59Gln	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.576C>A		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.176C>A	p.Pro59Gln	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
	ZCCHC2	ENST00000963441.1		c.176C>A	p.Pro59Gln	missense	Exon 1 of 14	ENSP00000633500.1
	ZCCHC2	ENST00000585873.5	TSL:1	n.-68C>A		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144992 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: 0.0000306

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000120 AC: 1 AN: 830526 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 387602

African (AFR) AF: 0.00 AC: 0 AN: 16616

American (AMR) AF: 0.00 AC: 0 AN: 3408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7614

East Asian (EAS) AF: 0.00 AC: 0 AN: 11192

South Asian (SAS) AF: 0.00 AC: 0 AN: 15632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1952

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 735858

Other (OTH) AF: 0.00 AC: 0 AN: 29896

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 144992 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 1 AN XY: 70472

African (AFR) AF: 0.00 AC: 0 AN: 40424

American (AMR) AF: 0.00 AC: 0 AN: 14672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.00 AC: 0 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000306 AC: 2 AN: 65364

Other (OTH) AF: 0.00 AC: 0 AN: 2000

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.23	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.26
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.27
Sift	Benign	0.086	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.78	P
Vest4		0.26
MutPred		0.20		Loss of glycosylation at P59 (P = 0.0075)
MVP		0.49
MPC		0.040
ClinPred		0.17	T
GERP RS		0.62
PromoterAI		-0.031	Neutral
Varity_R		0.060
gMVP		0.26

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: rs915021992; hg19: chr18-60190833;