rs187333111

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/19 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

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

PCARE-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 54
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PCARE links:

ENSG00000308575 (HGNC:):

ENSG00000308575 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 195107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCARE	NM_001029883.3 link	c.3739G>A	p.Gly1247Ser	missense_variant	Exon 2 of 2	ENST00000331664.6	NP_001025054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCARE	ENST00000331664.6 link	c.3739G>A	p.Gly1247Ser	missense_variant	Exon 2 of 2	2	NM_001029883.3	ENSP00000332809.4
ENSG00000308575	ENST00000835145.1 link	n.108+1102C>T		intron_variant	Intron 1 of 2
ENSG00000308575	ENST00000835146.1 link	n.91+1106C>T		intron_variant	Intron 1 of 2
ENSG00000308575	ENST00000835147.1 link	n.-41C>T		upstream_gene_variant

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

GnomAD2 exomes

AF:

0.00827

AC:

1470

AN:

177758

AF XY:

0.0102

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 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

African (AFR)

AF:

0.000650

AC:

AN:

32306

American (AMR)

AF:

0.00229

AC:

AN:

38850

Ashkenazi Jewish (ASJ)

AF:

0.00582

AC:

148

AN:

25444

East Asian (EAS)

AF:

0.000108

AC:

AN:

37004

South Asian (SAS)

AF:

0.0327

AC:

2660

AN:

81328

European-Finnish (FIN)

AF:

0.00199

AC:

101

AN:

50778

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

0.00623

AC:

6797

AN:

1091324

Other (OTH)

AF:

0.00702

AC:

413

AN:

58852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

665

1330

1996

2661

3326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152334

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41562

American (AMR)

AF:

0.00242

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4828

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00557

AC:

379

AN:

68036

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00554

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

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Dec 18, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Retinitis pigmentosa 54

Benign:2

Aug 30, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 26, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-2.1

PROVEAN

Benign

-0.84

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.034

ClinPred

0.0019

GERP RS

-7.2

Varity_R

0.023

gMVP

0.019

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over