rs1555408401

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-105368112-G-A
• chr14-105368112-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. 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 (★★). 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 12 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
• 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;