2-29072199-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001029883.3(PCARE):c.2063G>A(p.Cys688Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,614,218 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C688F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 44 hom. )

Consequence

PCARE
NM_001029883.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.333

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038235188).

BP6

Variant 2-29072199-C-T is Benign according to our data. Variant chr2-29072199-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193146.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00537 (818/152324) while in subpopulation AMR AF = 0.00948 (145/15294). AF 95% confidence interval is 0.00822. There are 0 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 44 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029883.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCARE	NM_001029883.3	MANE Select	c.2063G>A	p.Cys688Tyr	missense	Exon 1 of 2	NP_001025054.1	A6NGG8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCARE	ENST00000331664.6	TSL:2 MANE Select	c.2063G>A	p.Cys688Tyr	missense	Exon 1 of 2	ENSP00000332809.4	A6NGG8
ENSG00000308575	ENST00000835145.1		n.224+3032C>T		intron	N/A
ENSG00000308575	ENST00000835146.1		n.207+3032C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

818

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00738

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00504

AC:

1257

AN:

249574

AF XY:

0.00514

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00562

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.00723

Gnomad OTH exome

AF:

0.00528

GnomAD4 exome

AF:

0.00670

AC:

9797

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00650

AC XY:

4730

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00539

AC:

241

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

372

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000777

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00131

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00778

AC:

8646

AN:

1112012

Other (OTH)

AF:

0.00608

AC:

367

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

730

1460

2191

2921

3651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.00537

AC:

818

AN:

152324

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41572

American (AMR)

AF:

0.00948

AC:

145

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00738

AC:

502

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00666

Hom.:

Bravo

AF:

0.00554

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000947

AC:

ESP6500EA

AF:

0.00804

AC:

ExAC

AF:

0.00444

AC:

537

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00800

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa 54 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.036

Eigen

Benign

-0.047

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.59

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.1

PhyloP100

0.33

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.089

Sift

Benign

0.032

Sift4G

Uncertain

0.035

Polyphen

0.91

Vest4

0.33

MVP

0.46

MPC

0.044

ClinPred

0.052

GERP RS

4.8

Varity_R

0.22

gMVP

0.079

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over