chr18-62523527-T-C

Variant names:

• chr18-62523527-T-C
• rs1914153096
• NM_017742.6:c.103T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017742.6(ZCCHC2):​c.103T>C​(p.Ser35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S35A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000081 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZCCHC2 NM_017742.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.895
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047338814).

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.103T>C	p.Ser35Pro	missense	Exon 1 of 14	NP_060212.4
	ZCCHC2	NR_126534.2		n.503T>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.103T>C	p.Ser35Pro	missense	Exon 1 of 14	ENSP00000269499.4	Q9C0B9-1
	ZCCHC2	ENST00000963441.1		c.103T>C	p.Ser35Pro	missense	Exon 1 of 14	ENSP00000633500.1
	ZCCHC2	ENST00000585873.5	TSL:1	n.-141T>C		upstream_gene	N/A	ENSP00000468789.1	K7ESN2

Frequencies

GnomAD3 genomes AF: 0.00000809 AC: 1 AN: 123562 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000319

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000328 AC: 179 AN: 545014 Hom.: 0 Cov.: 5 AF XY: 0.000312 AC XY: 79 AN XY: 252952

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

African (AFR) AF: 0.000290 AC: 3 AN: 10342

American (AMR) AF: 0.00 AC: 0 AN: 656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 2400

South Asian (SAS) AF: 0.000277 AC: 3 AN: 10838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 188

Middle Eastern (MID) AF: 0.000947 AC: 1 AN: 1056

European-Non Finnish (NFE) AF: 0.000335 AC: 167 AN: 498298

Other (OTH) AF: 0.000281 AC: 5 AN: 17814

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000809 AC: 1 AN: 123602 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 59524

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

African (AFR) AF: 0.00 AC: 0 AN: 34366

American (AMR) AF: 0.00 AC: 0 AN: 12880

Ashkenazi Jewish (ASJ) AF: 0.000319 AC: 1 AN: 3134

East Asian (EAS) AF: 0.00 AC: 0 AN: 3286

South Asian (SAS) AF: 0.00 AC: 0 AN: 3344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58092

Other (OTH) AF: 0.00 AC: 0 AN: 1698

⚠️ 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

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	0.044
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.90
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.027
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.21		Loss of phosphorylation at S35 (P = 6e-04)
MVP		0.040
MPC		0.049
ClinPred		0.071	T
GERP RS		1.1
PromoterAI		0.037	Neutral
Varity_R		0.090
gMVP		0.092
Mutation Taster		=98/2	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: rs1914153096; hg19: chr18-60190760;