8-17184804-C-G

Variant names:

• chr8-17184804-C-G
• rs1468514577
• NM_016353.5:c.146C>G

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.146C>G​(p.Thr49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,550,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ZDHHC2 NM_016353.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47
• 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=0.12201288).

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.146C>G	p.Thr49Ser	missense	Exon 2 of 13	NP_057437.1	Q9UIJ5
	ZDHHC2	NM_001362988.2		c.27C>G	p.His9Gln	missense	Exon 2 of 14	NP_001349917.1
	ZDHHC2	NM_001362989.2		c.11C>G	p.Thr4Ser	missense	Exon 2 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.146C>G	p.Thr49Ser	missense	Exon 2 of 13	ENSP00000262096.8	Q9UIJ5
	ZDHHC2	ENST00000955296.1		c.192C>G	p.His64Gln	missense	Exon 3 of 15	ENSP00000625355.1
	ZDHHC2	ENST00000955297.1		c.146C>G	p.Thr49Ser	missense	Exon 2 of 12	ENSP00000625356.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398052 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 689678

⚠️ 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: 31470

American (AMR) AF: 0.00 AC: 0 AN: 35488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.00 AC: 0 AN: 78692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078358

Other (OTH) AF: 0.00 AC: 0 AN: 57920

⚠️ 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: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

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	0.097
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.10
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Polyphen		0.023	B
Vest4		0.22
MutPred		0.49		Gain of glycosylation at T49 (P = 0.0294)
MVP		0.58
MPC		0.019
ClinPred		0.13	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.32
Mutation Taster		=84/16	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: rs1468514577; hg19: chr8-17042313;