18-62523647-G-C

Variant names:

• chr18-62523647-G-C
• rs1441172295
• NM_017742.6:c.223G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017742.6(ZCCHC2):​c.223G>C​(p.Ala75Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000871 in 1,148,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527

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 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=0.0661315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6	c.223G>C	p.Ala75Pro	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4
ZCCHC2	NR_126534.2	n.623G>C		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.223G>C	p.Ala75Pro	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4
ZCCHC2	ENST00000588676.1	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 1	6		ENSP00000465548.1
ZCCHC2	ENST00000585873.5	n.-21G>C		upstream_gene_variant		1		ENSP00000468789.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.71e-7 AC: 1 AN: 1148136 Hom.: 0 Cov.: 70 AF XY: 0.00000180 AC XY: 1 AN XY: 554718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000261

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223G>C (p.A75P) alteration is located in exon 1 (coding exon 1) of the ZCCHC2 gene. This alteration results from a G to C substitution at nucleotide position 223, causing the alanine (A) at amino acid position 75 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	0.099
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.035
Sift	Benign	0.40	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.27		Gain of loop (P = 0.0097);
MVP		0.014
MPC		0.050
ClinPred		0.040	T
GERP RS		0.51
Varity_R		0.081
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: rs1441172295; hg19: chr18-60190880;