14-105314947-C-T

Position:

chr14-105314947-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001100913.3(PACS2):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000769 in 1,170,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PACS2
NM_001100913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.427

Variant links:

Genes affected

PACS2 (HGNC:23794): (phosphofurin acidic cluster sorting protein 2) Predicted to enable transmembrane transporter binding activity. Involved in endoplasmic reticulum calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and protein localization to plasma membrane. Acts upstream of or within protein localization to phagophore assembly site. Located in endoplasmic reticulum and mitochondrion. Implicated in developmental and epileptic encephalopathy 66. [provided by Alliance of Genome Resources, Apr 2022]

PACS2 links:

BRF1 (HGNC:11551): (BRF1 RNA polymerase III transcription initiation factor subunit) This gene encodes one of the three subunits of the RNA polymerase III transcription factor complex. This complex plays a central role in transcription initiation by RNA polymerase III on genes encoding tRNA, 5S rRNA, and other small structural RNAs. The gene product belongs to the TF2B family. Several alternatively spliced variants encoding different isoforms, that function at different promoters transcribed by RNA polymerase III, have been identified. [provided by RefSeq, Jun 2011]

BRF1 links:

PACS2 (HGNC:):

PACS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12709317).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS2	NM_001100913.3 linkuse as main transcript	c.29C>T	p.Pro10Leu	missense_variant	1/25	ENST00000447393.6	NP_001094383.2	Q86VP3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS2	ENST00000447393.6 linkuse as main transcript	c.29C>T	p.Pro10Leu	missense_variant	1/25	1	NM_001100913.3	ENSP00000393559.2		Q86VP3-2

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

146656

Hom.:

Cov.:

show subpopulations

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000153

AC:

AN:

65388

Hom.:

AF XY:

0.0000259

AC XY:

AN XY:

38626

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000409

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1023996

Hom.:

Cov.:

AF XY:

0.00000400

AC XY:

AN XY:

500462

show subpopulations

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:

0.00000811

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000136

AC:

AN:

146656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71362

show subpopulations

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:

0.0000304

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PACS2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the PACS2 protein (p.Pro10Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

N;N;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.033

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

0.0040

B;B;.

Vest4

0.14

MutPred

0.36

Gain of catalytic residue at G5 (P = 0.0074);Gain of catalytic residue at G5 (P = 0.0074);Gain of catalytic residue at G5 (P = 0.0074);

MVP

0.043

ClinPred

0.22

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.33

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