rs187333111

Positions:

chr2-29064997-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001029883.3(PCARE):c.3739G>A(p.Gly1247Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,573,766 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 93 hom. )

Consequence

PCARE
NM_001029883.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.07

Variant links:

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]

PCARE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017879605).

BP6

Variant 2-29064997-C-T is Benign according to our data. Variant chr2-29064997-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29064997-C-T is described in Lovd as [Benign]. Variant chr2-29064997-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00456 (695/152334) while in subpopulation SAS AF= 0.0329 (159/4828). AF 95% confidence interval is 0.0288. There are 4 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCARE	NM_001029883.3 linkuse as main transcript	c.3739G>A	p.Gly1247Ser	missense_variant	2/2	ENST00000331664.6	NP_001025054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCARE	ENST00000331664.6 linkuse as main transcript	c.3739G>A	p.Gly1247Ser	missense_variant	2/2	2	NM_001029883.3	ENSP00000332809.4		A6NGG8

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00827

AC:

1470

AN:

177758

Hom.:

AF XY:

0.0102

AC XY:

979

AN XY:

95702

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00598

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0328

Gnomad FIN exome

AF:

0.00184

Gnomad NFE exome

AF:

0.00668

Gnomad OTH exome

AF:

0.00625

GnomAD4 exome

AF:

0.00724

AC:

10297

AN:

1421432

Hom.:

Cov.:

AF XY:

0.00802

AC XY:

5642

AN XY:

703582

show subpopulations

Gnomad4 AFR exome

AF:

0.000650

Gnomad4 AMR exome

AF:

0.00229

Gnomad4 ASJ exome

AF:

0.00582

Gnomad4 EAS exome

AF:

0.000108

Gnomad4 SAS exome

AF:

0.0327

Gnomad4 FIN exome

AF:

0.00199

Gnomad4 NFE exome

AF:

0.00623

Gnomad4 OTH exome

AF:

0.00702

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152334

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0329

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00557

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00534

Hom.:

Bravo

AF:

0.00388

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00126

AC:

ESP6500EA

AF:

0.00555

AC:

ExAC

AF:

0.00717

AC:

853

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Retinitis pigmentosa 54

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 26, 2015	- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0060

DANN

Benign

0.53

DEOGEN2

Benign

0.0017

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0050

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.95

PROVEAN

Benign

-0.84

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.034

MVP

0.076

MPC

0.013

ClinPred

0.0019

GERP RS

-7.2

Varity_R

0.023

gMVP

0.019

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over