2-29072199-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.333

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 -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 id is 193146.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCARE	NM_001029883.3	c.2063G>A	p.Cys688Tyr	missense_variant	1/2	ENST00000331664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCARE	ENST00000331664.6	c.2063G>A	p.Cys688Tyr	missense_variant	1/2	2	NM_001029883.3	P1

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 818 AN: 152206 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00504 AC: 1257 AN: 249574 Hom.: 4 AF XY: 0.00514 AC XY: 696 AN XY: 135398

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 SAS exome AF: 0.000784

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.: 44 Cov.: 51 AF XY: 0.00650 AC XY: 4730 AN XY: 727248

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00778

Gnomad4 OTH exome AF: 0.00608

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74484

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00738

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00704 Hom.: 3

Bravo AF: 0.00554

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000947 AC: 4

ESP6500EA AF: 0.00804 AC: 68

ExAC AF: 0.00444 AC: 537

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00800

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PCARE: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 08, 2014

- -

Retinitis pigmentosa 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 17, 2020

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Benign	0.71
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.089
Sift	Benign	0.032	D
Sift4G	Uncertain	0.035	D
Polyphen		0.91	P
Vest4		0.33
MVP		0.46
MPC		0.044
ClinPred		0.052	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.079

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: rs149601594; hg19: chr2-29295065;