10-84194769-CT-C

Variant names:

• chr10-84194769-CT-C
• NM_033100.4:c.10delT

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.10delT​(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 39 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 rank	MANE	Protein	UniProt
CDHR1	NM_033100.4	c.10delT	p.Cys4AlafsTer47	frameshift_variant	Exon 1 of 17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.10delT	p.Cys4AlafsTer47	frameshift_variant	Exon 1 of 17	1	NM_033100.4	ENSP00000485478.1
CDHR1	ENST00000332904.7	c.10delT	p.Cys4AlafsTer47	frameshift_variant	Exon 1 of 17	1		ENSP00000331063.3

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

Jan 25, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Jun 01, 2021

DBGen Ocular Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;