Genetic Variant PACS2:p.Glu209Gln (chr14-105368112-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_001100913.3(PACS2):c.625G>C(p.Glu209Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E209K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PACS2
NM_001100913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.67

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 66
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

PACS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_001100913.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-105368112-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.37606448).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100913.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PACS2	NM_001100913.3	MANE Select	c.625G>C	p.Glu209Gln	missense	Exon 6 of 25	NP_001094383.2	Q86VP3-2
PACS2	NM_015197.4		c.625G>C	p.Glu209Gln	missense	Exon 6 of 24	NP_056012.2	Q86VP3-1
PACS2	NM_001243127.3		c.424G>C	p.Glu142Gln	missense	Exon 6 of 24	NP_001230056.1	Q86VP3-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PACS2	ENST00000447393.6	TSL:1 MANE Select	c.625G>C	p.Glu209Gln	missense	Exon 6 of 25	ENSP00000393559.2	Q86VP3-2
PACS2	ENST00000325438.12	TSL:1	c.625G>C	p.Glu209Gln	missense	Exon 6 of 24	ENSP00000321834.8	Q86VP3-1
PACS2	ENST00000430725.6	TSL:1	c.424G>C	p.Glu142Gln	missense	Exon 6 of 24	ENSP00000393524.2	Q86VP3-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.020

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.1

PhyloP100

9.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.2

REVEL

Benign

0.20

Sift

Benign

0.045

Sift4G

Uncertain

0.032

Polyphen

0.80

Vest4

0.59

MutPred

0.12

Gain of catalytic residue at F206 (P = 0.0409)

MVP

0.39

ClinPred

0.97

GERP RS

4.1

Varity_R

0.32

gMVP

0.22

Mutation Taster

=40/60

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over