17-76540154-C-G

Position:

chr17-76540154-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting

The NM_001077620.3(PRCD):c.13C>G(p.Leu5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,603,570 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 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

PRCD
NM_001077620.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.189

Variant links:

Genes affected

PRCD (HGNC:32528): (photoreceptor disc component) This gene is predominantly expressed in the retina, and mutations in this gene are the cause of autosomal recessive retinal degeneration in both humans and dogs. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2010]

PRCD links:

CYGB (HGNC:16505): (cytoglobin) This gene encodes a globin protein found in vertebrate cells. The encoded protein is described as a hexacoordinate hemoglobin which binds ligand differently from the pentacoordinate hemoglobins involved in oxygen transport, and may be involved in protection during oxidative stress. This gene is located on chromosome 17 in the same region as a retinal gene which is mutated in progressive rod-cone degeneration, but in the opposite orientation. [provided by RefSeq, Jan 2012]

CYGB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a chain Photoreceptor disk component PRCD (size 53) in uniprot entity PRCD_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001077620.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15381199).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000127 (19/150006) while in subpopulation NFE AF= 0.000221 (15/67756). AF 95% confidence interval is 0.000135. There are 0 homozygotes in gnomad4. There are 3 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	Protein	UniProt
PRCD	NM_001077620.3 linkuse as main transcript	c.13C>G	p.Leu5Val	missense_variant	1/5	ENST00000592014.6	NP_001071088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRCD	ENST00000592014.6 linkuse as main transcript	c.13C>G	p.Leu5Val	missense_variant	1/5	1	NM_001077620.3	ENSP00000467661	P1

Frequencies

GnomAD3 genomes

AF:

0.000127

AC:

AN:

149886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000735

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

233620

Hom.:

AF XY:

0.000150

AC XY:

AN XY:

127052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000240

AC:

349

AN:

1453564

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

150

AN XY:

722142

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000310

Gnomad4 OTH exome

AF:

0.0000666

GnomAD4 genome

AF:

0.000127

AC:

AN:

150006

Hom.:

Cov.:

AF XY:

0.0000411

AC XY:

AN XY:

73026

show subpopulations

Gnomad4 AFR

AF:

0.0000733

Gnomad4 AMR

AF:

0.0000680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The c.13C>G (p.L5V) alteration is located in exon 1 (coding exon 1) of the PRCD gene. This alteration results from a C to G substitution at nucleotide position 13, causing the leucine (L) at amino acid position 5 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the PRCD protein (p.Leu5Val). This variant is present in population databases (rs200954045, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PRCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 891110). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.0060

Eigen_PC

Benign

-0.031

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.53

.;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.51

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.83

P;P

Vest4

0.16

MVP

0.38

MPC

0.34

ClinPred

0.25

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.47

gMVP

0.076

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