14-60115299-C-A

Position:

• chr14-60115299-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330177.2(PCNX4):​c.1195C>A​(p.Leu399Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCNX4 NM_001330177.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

Genes affected

PCNX4 (HGNC:20349): (pecanex 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.16232508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNX4	NM_001330177.2	c.1195C>A	p.Leu399Ile	missense_variant	4/11	ENST00000406854.6
PCNX4	NM_022495.5	c.493C>A	p.Leu165Ile	missense_variant	3/10
PCNX4	XM_047431699.1	c.1195C>A	p.Leu399Ile	missense_variant	4/11
PCNX4	XM_047431700.1	c.1195C>A	p.Leu399Ile	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNX4	ENST00000406854.6	c.1195C>A	p.Leu399Ile	missense_variant	4/11	5	NM_001330177.2	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456150 Hom.: 0 Cov.: 49 AF XY: 0.00000138 AC XY: 1 AN XY: 724338

Gnomad4 AFR exome AF: 0.00

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000370 Hom.: 0

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

Oct 06, 2021

The c.493C>A (p.L165I) alteration is located in exon 3 (coding exon 2) of the PCNX4 gene. This alteration results from a C to A substitution at nucleotide position 493, causing the leucine (L) at amino acid position 165 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0094	.;T;T
Eigen	Benign	0.028
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.042
Sift	Uncertain	0.027	D;D;D
Sift4G	Benign	0.086	T;T;T
Polyphen		0.52, 0.66	.;P;P
Vest4		0.28
MutPred		0.37		.;Loss of catalytic residue at L399 (P = 0.0056);.;
MVP		0.18
MPC		0.025
ClinPred		0.46	T
GERP RS		2.5
Varity_R		0.078
gMVP		0.42

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

Other links and lift over

dbSNP: rs1280060913; hg19: chr14-60582017;