18-62523518-A-C

Variant names:

• chr18-62523518-A-C
• rs1914151545
• NM_017742.6:c.94A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017742.6(ZCCHC2):​c.94A>C​(p.Lys32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 131,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. K32E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07443231).

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.94A>C	p.Lys32Gln	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.494A>C		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.94A>C	p.Lys32Gln	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
	ZCCHC2	ENST00000963441.1		c.94A>C	p.Lys32Gln	missense	Exon 1 of 14	ENSP00000633500.1
	ZCCHC2	ENST00000585873.5	TSL:1	n.-150A>C		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 201 AN: 131368 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00124

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.000312

Gnomad EAS AF: 0.00776

Gnomad SAS AF: 0.00814

Gnomad FIN AF: 0.00252

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000820

Gnomad OTH AF: 0.000543

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00394 AC: 2018 AN: 511852 Hom.: 0 Cov.: 5 AF XY: 0.00379 AC XY: 904 AN XY: 238734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00372 AC: 36 AN: 9670

American (AMR) AF: 0.00 AC: 0 AN: 672

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 13 AN: 3262

East Asian (EAS) AF: 0.00562 AC: 13 AN: 2314

South Asian (SAS) AF: 0.00430 AC: 46 AN: 10704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 242

Middle Eastern (MID) AF: 0.00611 AC: 6 AN: 982

European-Non Finnish (NFE) AF: 0.00395 AC: 1844 AN: 467280

Other (OTH) AF: 0.00359 AC: 60 AN: 16726

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00150 AC: 197 AN: 131402 Hom.: 0 Cov.: 28 AF XY: 0.00159 AC XY: 101 AN XY: 63430

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00133 AC: 49 AN: 36908

American (AMR) AF: 0.00168 AC: 23 AN: 13676

Ashkenazi Jewish (ASJ) AF: 0.000312 AC: 1 AN: 3210

East Asian (EAS) AF: 0.00779 AC: 29 AN: 3724

South Asian (SAS) AF: 0.00733 AC: 27 AN: 3684

European-Finnish (FIN) AF: 0.00252 AC: 16 AN: 6352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000820 AC: 50 AN: 60956

Other (OTH) AF: 0.000540 AC: 1 AN: 1852

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.038
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.26	T
Polyphen		0.35	B
Vest4		0.11
MutPred		0.17		Loss of methylation at K32 (P = 0.0058)
MVP		0.095
MPC		0.044
ClinPred		0.30	T
GERP RS		0.21
PromoterAI		0.38	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.14
Mutation Taster		=97/3	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: rs1914151545; hg19: chr18-60190751;