Variant chr14-77139612-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_174976.2(ZDHHC22):c.127C>G(p.Leu43Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZDHHC22
NM_174976.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.40

Variant links:

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]

ZDHHC22 links:

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]

TMEM63C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26092967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZDHHC22	NM_174976.2 linkuse as main transcript	c.127C>G	p.Leu43Val	missense_variant	2/3	ENST00000319374.4	NP_777636.2
ZDHHC22	NM_001364172.1 linkuse as main transcript	c.127C>G	p.Leu43Val	missense_variant	2/3		NP_001351101.1
ZDHHC22	XM_011536661.3 linkuse as main transcript	c.127C>G	p.Leu43Val	missense_variant	2/3		XP_011534963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZDHHC22	ENST00000319374.4 linkuse as main transcript	c.127C>G	p.Leu43Val	missense_variant	2/3	1	NM_174976.2	ENSP00000318222	P1
ZDHHC22	ENST00000555389.1 linkuse as main transcript	c.127C>G	p.Leu43Val	missense_variant	2/2	4		ENSP00000451337
TMEM63C	ENST00000557408.5 linkuse as main transcript	c.-237+22770G>C		intron_variant		4		ENSP00000450879
ZDHHC22	ENST00000555327.1 linkuse as main transcript			downstream_gene_variant		2		ENSP00000450478

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152220

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432010

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74494

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.127C>G (p.L43V) alteration is located in exon 2 (coding exon 1) of the ZDHHC22 gene. This alteration results from a C to G substitution at nucleotide position 127, causing the leucine (L) at amino acid position 43 to be replaced by a valine (V). 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

Benign

0.084

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.041

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.021

D;D

Sift4G

Benign

0.13

T;.

Polyphen

0.90

P;.

Vest4

0.49

MutPred

0.31

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.26

MPC

0.97

ClinPred

0.78

GERP RS

5.7

Varity_R

0.27

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over