14-77133841-G-C

Position:

• chr14-77133841-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_174976.2(ZDHHC22):​c.634C>G​(p.Arg212Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZDHHC22 NM_174976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

Genes affected

ZDHHC22 (HGNC:20106): (zinc finger DHHC-type palmitoyltransferase 22) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Involved in protein localization to plasma membrane and protein palmitoylation. Located in Golgi apparatus; endoplasmic reticulum; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259164 (HGNC:):

TMEM63C (HGNC:23787): (transmembrane protein 63C) Enables calcium activated cation channel activity. Involved in cation transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Biomarker of focal segmental glomerulosclerosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZDHHC22	NM_174976.2	c.634C>G	p.Arg212Gly	missense_variant	3/3	ENST00000319374.4	NP_777636.2
ZDHHC22	NM_001364172.1	c.634C>G	p.Arg212Gly	missense_variant	3/3		NP_001351101.1
ZDHHC22	XM_011536661.3	c.634C>G	p.Arg212Gly	missense_variant	3/3		XP_011534963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZDHHC22	ENST00000319374.4	c.634C>G	p.Arg212Gly	missense_variant	3/3	1	NM_174976.2	ENSP00000318222.4
ENSG00000259164	ENST00000557752.1	n.136+27997G>C		intron_variant		5		ENSP00000456507.1
TMEM63C	ENST00000557408.5	c.-237+16999G>C		intron_variant		4		ENSP00000450879.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.634C>G (p.R212G) alteration is located in exon 3 (coding exon 2) of the ZDHHC22 gene. This alteration results from a C to G substitution at nucleotide position 634, causing the arginine (R) at amino acid position 212 to be replaced by a glycine (G). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.54		Loss of MoRF binding (P = 0.0155);
MVP		0.16
MPC		1.5
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.25
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-77600184;