rs756678484

Positions:

• chr10-84211138-AG-A
• chr10-84211138-AG-AGG

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.1463del​(p.Gly488AlafsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G487G) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CDHR1 NM_033100.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-84211138-AG-A is Pathogenic according to our data. Variant chr10-84211138-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 438116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-84211138-AG-A is described in Lovd as [Pathogenic]. Variant chr10-84211138-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr10-84211138-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDHR1	NM_033100.4	c.1463del	p.Gly488AlafsTer20	frameshift_variant	13/17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.1463del	p.Gly488AlafsTer20	frameshift_variant	13/17	1	NM_033100.4	ENSP00000485478	P2
CDHR1	ENST00000332904.7	c.1463del	p.Gly488AlafsTer20	frameshift_variant	13/17	1		ENSP00000331063	A2
CDHR1	ENST00000372117.6	c.701-505del		intron_variant		2		ENSP00000361189
CDHR1	ENST00000622973.1	c.196del	p.Gly66AlafsTer20	frameshift_variant, NMD_transcript_variant	2/6	5		ENSP00000485151

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251426 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135890

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: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 727240

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: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30487145, 32581362, 20087419, 27623334, 28418496) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 30, 2023	This variant is present in population databases (rs756678484, gnomAD 0.05%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438116). This variant is also known as c.1459delG, p.G487GfsX20. This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 27623334, 28418496). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gly488Alafs*20) in the CDHR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDHR1 are known to be pathogenic (PMID: 23044944, 23591405, 26103963, 26261414). -

Retinitis pigmentosa 65 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2010

- -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs756678484; hg19: chr10-85970894;