chr14-105314207-C-A

Position:

• chr14-105314207-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001243127.3(PACS2):​c.-83+13228C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 150,072 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.045 (540 hom., cov: 33)
• Consequence: PACS2 NM_001243127.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-105314207-C-A is Benign according to our data. Variant chr14-105314207-C-A is described in ClinVar as [Benign]. Clinvar id is 1246245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS2	NM_001243127.3	c.-83+13228C>A		intron_variant			NP_001230056.1
BRF1	NM_001242786.2	c.-162+1115G>T		intron_variant			NP_001229715.1
BRF1	NM_001242787.2	c.-162+1115G>T		intron_variant			NP_001229716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS2	ENST00000430725.6	c.-83+13228C>A		intron_variant		1		ENSP00000393524.2
BRF1	ENST00000440513.7	c.-162+1115G>T		intron_variant		2		ENSP00000388877.3
BRF1	ENST00000327359.7	c.-162+1115G>T		intron_variant		2		ENSP00000329029.3
BRF1	ENST00000550692.1	c.-162+1135G>T		intron_variant		4		ENSP00000448823.1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6787 AN: 149966 Hom.: 540 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.0000982

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.000385

Gnomad OTH AF: 0.0266

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0454 AC: 6809 AN: 150072 Hom.: 540 Cov.: 33 AF XY: 0.0434 AC XY: 3179 AN XY: 73276

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.0000982

Gnomad4 NFE AF: 0.000385

Gnomad4 OTH AF: 0.0263

Alfa AF: 0.00914 Hom.: 16

Bravo AF: 0.0513

Asia WGS AF: 0.00925 AC: 33 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.81

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113540988; hg19: chr14-105780544;