14-105314935-G-T

Position:

• chr14-105314935-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001100913.3(PACS2):​c.17G>T​(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,129,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PACS2 NM_001100913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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]

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]

PACS2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20111212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS2	NM_001100913.3	c.17G>T	p.Arg6Leu	missense_variant	1/25	ENST00000447393.6	NP_001094383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS2	ENST00000447393.6	c.17G>T	p.Arg6Leu	missense_variant	1/25	1	NM_001100913.3	ENSP00000393559.2

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145826 Hom.: 0 Cov.: 31

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000407 AC: 4 AN: 983894 Hom.: 0 Cov.: 20 AF XY: 0.00000418 AC XY: 2 AN XY: 478694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000686 AC: 1 AN: 145826 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 1 AN XY: 70922

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: 0.0000152

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

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. ClinVar contains an entry for this variant (Variation ID: 1522559). This variant has not been reported in the literature in individuals affected with PACS2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 6 of the PACS2 protein (p.Arg6Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.96	D;B;.
Vest4		0.20
MutPred		0.33		Loss of methylation at R6 (P = 0.0028);Loss of methylation at R6 (P = 0.0028);Loss of methylation at R6 (P = 0.0028);
MVP		0.068
ClinPred		0.45	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.38

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

Other links and lift over

dbSNP: rs1330015149; hg19: chr14-105781272;