10-84211138-AGG-AGGG

Variant names:

• chr10-84211138-A-AG
• rs756678484
• NM_033100.4:c.1463dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_033100.4(CDHR1):​c.1463dupG​(p.Ser489LeufsTer47) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G488G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDHR1 NM_033100.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.51
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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-A-AG is Pathogenic according to our data. Variant chr10-84211138-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 1069264.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	NM_033100.4	MANE Select	c.1463dupG	p.Ser489LeufsTer47	frameshift	Exon 13 of 17	NP_149091.1
	CDHR1	NM_001171971.3		c.1463dupG	p.Ser489LeufsTer47	frameshift	Exon 13 of 17	NP_001165442.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	ENST00000623527.4	TSL:1 MANE Select	c.1463dupG	p.Ser489LeufsTer47	frameshift	Exon 13 of 17	ENSP00000485478.1
	CDHR1	ENST00000332904.7	TSL:1	c.1463dupG	p.Ser489LeufsTer47	frameshift	Exon 13 of 17	ENSP00000331063.3
	CDHR1	ENST00000622973.1	TSL:5	n.194dupG		non_coding_transcript_exon	Exon 2 of 6	ENSP00000485151.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in CDHR1 are known to be pathogenic (PMID: 23044944, 23591405, 26103963, 26261414). This variant has not been reported in the literature in individuals with CDHR1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser489Leufs*47) in the CDHR1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756678484; hg19: chr10-85970894; COSMIC: COSV100258759; COSMIC: COSV100258759;