18-62523519-A-C

Variant names:

• chr18-62523519-A-C
• rs1914151788
• NM_017742.6:c.95A>C

Variant summary

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

The NM_017742.6(ZCCHC2):​c.95A>C​(p.Lys32Thr) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00092 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.111

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06422919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC2	NM_017742.6	c.95A>C	p.Lys32Thr	missense_variant	Exon 1 of 14	ENST00000269499.10	NP_060212.4
ZCCHC2	NR_126534.2	n.495A>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.95A>C	p.Lys32Thr	missense_variant	Exon 1 of 14	5	NM_017742.6	ENSP00000269499.4
ZCCHC2	ENST00000585873.5	n.-149A>C		upstream_gene_variant		1		ENSP00000468789.1
ZCCHC2	ENST00000588676.1	c.-101A>C		upstream_gene_variant		6		ENSP00000465548.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 44 AN: 129666 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000671

Gnomad ASJ AF: 0.000312

Gnomad EAS AF: 0.00256

Gnomad SAS AF: 0.00141

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000554

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000921 AC: 684 AN: 742512 Hom.: 0 Cov.: 28 AF XY: 0.000953 AC XY: 328 AN XY: 344012

Gnomad4 AFR exome AF: 0.000993

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.000655

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000929

Gnomad4 OTH exome AF: 0.000739

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000347 AC: 45 AN: 129710 Hom.: 0 Cov.: 28 AF XY: 0.000446 AC XY: 28 AN XY: 62794

Gnomad4 AFR AF: 0.000247

Gnomad4 AMR AF: 0.000670

Gnomad4 ASJ AF: 0.000312

Gnomad4 EAS AF: 0.00257

Gnomad4 SAS AF: 0.00141

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000549

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95A>C (p.K32T) alteration is located in exon 1 (coding exon 1) of the ZCCHC2 gene. This alteration results from a A to C substitution at nucleotide position 95, causing the lysine (K) at amino acid position 32 to be replaced by a threonine (T). 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	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.0080
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.069	B
Vest4		0.16
MutPred		0.24		Gain of phosphorylation at K32 (P = 0.0053);
MVP		0.048
MPC		0.047
ClinPred		0.20	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.16

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: rs1914151788; hg19: chr18-60190752;