14-105368112-G-C

Variant names:

• chr14-105368112-G-C
• rs1555408401
• NM_001100913.3:c.625G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.67
• Publications: 1 publications found

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):

• developmental and epileptic encephalopathy, 66

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PACS2	NM_001100913.3	c.625G>C	p.Glu209Gln	missense_variant	Exon 6 of 25	ENST00000447393.6	NP_001094383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACS2	ENST00000447393.6	c.625G>C	p.Glu209Gln	missense_variant	Exon 6 of 25	1	NM_001100913.3	ENSP00000393559.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 209 of the PACS2 protein (p.Glu209Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PACS2-related conditions. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Glu209 amino acid residue in PACS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29656858). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PACS2: PM2, PM5

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	.;M;M;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.045	D;T;D;T
Sift4G	Uncertain	0.032	D;T;D;D
Vest4		0.59
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.32
gMVP		0.22
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1555408401; hg19: chr14-105834449;