rs146455733

chr2-29074163-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001029883.3(PCARE):c.99G>A(p.Gln33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,610,772 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: PCARE NM_001029883.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.178

Genes affected

PCARE (HGNC:34383): (photoreceptor cilium actin regulator) The protein encoded by this gene is highly expressed in photoreceptors and may associate with the primary cilium of the outer segment. The encoded protein appears to undergo post-translational lipid modification. Nonsense and missense variants of this gene appear to cause a recessive form of retinitis pigmentosa. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-29074163-C-T is Benign according to our data. Variant chr2-29074163-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285034.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.178 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (159/152320) while in subpopulation NFE AF= 0.00165 (112/68034). AF 95% confidence interval is 0.0014. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCARE	NM_001029883.3	c.99G>A	p.Gln33=	synonymous_variant	1/2	ENST00000331664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCARE	ENST00000331664.6	c.99G>A	p.Gln33=	synonymous_variant	1/2	2	NM_001029883.3	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00153 AC: 381 AN: 248272 Hom.: 2 AF XY: 0.00148 AC XY: 199 AN XY: 134704

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00330

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1458452 Hom.: 4 Cov.: 37 AF XY: 0.00122 AC XY: 887 AN XY: 725024

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00403

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000813

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000900 AC XY: 67 AN XY: 74480

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.000880

EpiCase AF: 0.00147

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PCARE: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.0
Dann	Benign	0.54

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: rs146455733; hg19: chr2-29297029;