10-84194761-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The NM_033100.4(CDHR1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,519,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CDHR1
NM_033100.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 2.51

Variant links:

Genes affected

CDHR1 (HGNC:14550): (cadherin related family member 1) This gene belongs to the cadherin superfamily of calcium-dependent cell adhesion molecules. The encoded protein is a photoreceptor-specific cadherin that plays a role in outer segment disc morphogenesis. Mutations in this gene are associated with inherited retinal dystrophies. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2013]

CDHR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_033100.4 (CDHR1) was described as [Pathogenic] in ClinVar as 812258

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-84194761-A-G is Pathogenic according to our data. Variant chr10-84194761-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193474.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=1}. Variant chr10-84194761-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR1	NM_033100.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/17	ENST00000623527.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR1	ENST00000623527.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/17	1	NM_033100.4	P2	Q96JP9-1
CDHR1	ENST00000332904.7 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/17	1		A2	Q96JP9-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

116880

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64500

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:

0.0000464

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000271

AC:

AN:

1367378

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

674492

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000345

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 05, 2023	Disruption of the initiator codon has been observed in individuals with retinal dystrophy (PMID: 26306921, 32037395, 32681094; Invitae). This sequence change affects the initiator methionine of the CDHR1 mRNA. The next in-frame methionine is located at codon 39. This variant is present in population databases (rs794726954, gnomAD 0.005%). ClinVar contains an entry for this variant (Variation ID: 193474). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	Described in an individual with adult-onset macular dystrophy and reduced visual acuity who also harbored a synonymous variant in CDHR1 in published literature (Ba-Abbad et al., 2020); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32681094) -

Cone-rod dystrophy 15

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jun 01, 2021

- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Met1? variant in CDHR1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.069

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.028

B;B

Vest4

0.78

MutPred

0.95

Loss of catalytic residue at M1 (P = 0.0029);Loss of catalytic residue at M1 (P = 0.0029);

MVP

0.35

ClinPred

0.72

GERP RS

2.8

Varity_R

0.45

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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