10-84194769-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033100.4(CDHR1):c.10del(p.Cys4AlafsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDHR1 NM_033100.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.734

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 71 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-84194769-CT-C is Pathogenic according to our data. Variant chr10-84194769-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1213967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR1	NM_033100.4	c.10del	p.Cys4AlafsTer47	frameshift_variant	1/17	ENST00000623527.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR1	ENST00000623527.4	c.10del	p.Cys4AlafsTer47	frameshift_variant	1/17	1	NM_033100.4	P2
CDHR1	ENST00000332904.7	c.10del	p.Cys4AlafsTer47	frameshift_variant	1/17	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 15 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Cys4AlafsTer47 variant in CDHR1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 194793), in one individual with cone-rod dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 194793); however, the phase of these variants is unknown at this time. The p.Cys4AlafsTer47 variant in CDHR1 has not been previously reported in individuals with autosomal recessive cone-rod dystrophy 15. This variant has also been reported in ClinVar (Variation ID: 1213967) and has been interpreted as likely pathogenic by DBGen Ocular Genomics. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 4 and leads to a premature termination codon 47 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CDHR1 gene is an established disease mechanism in autosomal recessive cone-rod dystrophy 15. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cone-rod dystrophy 15. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	DBGen Ocular Genomics	Jun 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-85954525;