14-105368112-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PP5_Very_Strong

The NM_001100913.3(PACS2):​c.625G>A​(p.Glu209Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003920843: Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018).; SCV005416176: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV001873688: Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); SCV001444087: Functional analysis using co-immunoprecipitation analysis demonstrated that the p.E209K alteration causes PACS2 to increase interaction to three target proteins, histone deacetylases SIRT1 and HDAC1 and ion channel TRPV1, to a greater extent than wild type suggesting this alteration interferes with autoregulation of protein function (Olson HE, 2018).; SCV005352201: In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. PMID:30290155; SCV005900623: Functional studies indicate that the c.625G>A (p.Glu209Lys) variant alters binding of PACS2 to one or more of its interacting proteins critical for neurogenesis, neuronal communication, and cerebellar development (PMID:29656858, 36188273).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E209Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PACS2 NM_001100913.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38
• 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):

• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003920843: Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018).; SCV005416176: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV001873688: Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); SCV001444087: Functional analysis using co-immunoprecipitation analysis demonstrated that the p.E209K alteration causes PACS2 to increase interaction to three target proteins, histone deacetylases SIRT1 and HDAC1 and ion channel TRPV1, to a greater extent than wild type suggesting this alteration interferes with autoregulation of protein function (Olson HE, 2018).; SCV005352201: In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. PMID:30290155; SCV005900623: Functional studies indicate that the c.625G>A (p.Glu209Lys) variant alters binding of PACS2 to one or more of its interacting proteins critical for neurogenesis, neuronal communication, and cerebellar development (PMID: 29656858, 36188273).
• 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
• PP5: Variant 14-105368112-G-A is Pathogenic according to our data. 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS2	NM_001100913.3	MANE Select	c.625G>A	p.Glu209Lys	missense	Exon 6 of 25	NP_001094383.2	Q86VP3-2
	PACS2	NM_015197.4		c.625G>A	p.Glu209Lys	missense	Exon 6 of 24	NP_056012.2	Q86VP3-1
	PACS2	NM_001243127.3		c.424G>A	p.Glu142Lys	missense	Exon 6 of 24	NP_001230056.1	Q86VP3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS2	ENST00000447393.6	TSL:1 MANE Select	c.625G>A	p.Glu209Lys	missense	Exon 6 of 25	ENSP00000393559.2	Q86VP3-2
	PACS2	ENST00000325438.12	TSL:1	c.625G>A	p.Glu209Lys	missense	Exon 6 of 24	ENSP00000321834.8	Q86VP3-1
	PACS2	ENST00000430725.6	TSL:1	c.424G>A	p.Glu142Lys	missense	Exon 6 of 24	ENSP00000393524.2	Q86VP3-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
22	-	-	Developmental and epileptic encephalopathy, 66 (22)
9	-	-	not provided (9)
2	-	-	PACS2-related disorder (2)
1	-	-	Developmental and epileptic encephalopathy, 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	See cases (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.23
Sift	Benign	0.042	D
Sift4G	Uncertain	0.039	D
Polyphen		0.76	P
Vest4		0.75
MutPred		0.20		Gain of ubiquitination at E209 (P = 0)
MVP		0.24
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.50
gMVP		0.26
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV100330680; COSMIC: COSV100330680;