2-29061832-C-T

Position:

• chr2-29061832-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001029883.3(PCARE):​c.*3037G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 152,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCARE NM_001029883.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.376

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (253/152290) while in subpopulation NFE AF= 0.00319 (217/68024). AF 95% confidence interval is 0.00284. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCARE	NM_001029883.3	c.*3037G>A		3_prime_UTR_variant	2/2	ENST00000331664.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCARE	ENST00000331664.6	c.*3037G>A		3_prime_UTR_variant	2/2	2	NM_001029883.3	P1
PCARE	ENST00000602958.1	n.324G>A		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74462

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00152

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.73

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: rs569687522; hg19: chr2-29284698;