8-17186333-G-C

Variant names:

• chr8-17186333-G-C
• rs375924295
• NM_016353.5:c.160G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016353.5(ZDHHC2):​c.160G>C​(p.Val54Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,742 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. V54M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZDHHC2 NM_016353.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 1 publications found

Genes affected

ZDHHC2 (HGNC:18469): (zinc finger DHHC-type palmitoyltransferase 2) Enables protein homodimerization activity and protein-cysteine S-palmitoyltransferase activity. Involved in several processes, including peptidyl-L-cysteine S-palmitoylation; regulation of protein catabolic process; and regulation of protein localization to plasma membrane. Located in Golgi apparatus and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18527493).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016353.5. 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
	ZDHHC2	NM_016353.5	MANE Select	c.160G>C	p.Val54Leu	missense splice_region	Exon 3 of 13	NP_057437.1	Q9UIJ5
	ZDHHC2	NM_001362988.2		c.41G>C	p.Cys14Ser	missense splice_region	Exon 3 of 14	NP_001349917.1
	ZDHHC2	NM_001362989.2		c.25G>C	p.Val9Leu	missense splice_region	Exon 3 of 13	NP_001349918.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC2	ENST00000262096.13	TSL:1 MANE Select	c.160G>C	p.Val54Leu	missense splice_region	Exon 3 of 13	ENSP00000262096.8	Q9UIJ5
	ZDHHC2	ENST00000955296.1		c.206G>C	p.Cys69Ser	missense splice_region	Exon 4 of 15	ENSP00000625355.1
	ZDHHC2	ENST00000955297.1		c.160G>C	p.Val54Leu	missense splice_region	Exon 3 of 12	ENSP00000625356.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000440 AC: 1 AN: 227154 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436742 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 714482

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

African (AFR) AF: 0.00 AC: 0 AN: 32606

American (AMR) AF: 0.00 AC: 0 AN: 41080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 38536

South Asian (SAS) AF: 0.00 AC: 0 AN: 82052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099272

Other (OTH) AF: 0.00 AC: 0 AN: 59272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.072
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Polyphen		0.0040	B
Vest4		0.33
MutPred		0.34		Loss of helix (P = 0.3949)
MVP		0.56
MPC		0.020
ClinPred		0.24	T
GERP RS		2.7
Varity_R		0.083
gMVP		0.60
Mutation Taster		=74/26	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: rs375924295; hg19: chr8-17043842;