rs786205459

Positions:

• chr10-84211698-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000623527.4(CDHR1):​c.1536T>A​(p.Tyr512Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDHR1 ENST00000623527.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0120

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 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 10-84211698-T-A is Pathogenic according to our data. Variant chr10-84211698-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191005.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-84211698-T-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.1536T>A	p.Tyr512Ter	stop_gained	14/17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.1536T>A	p.Tyr512Ter	stop_gained	14/17	1	NM_033100.4	ENSP00000485478	P2
CDHR1	ENST00000332904.7	c.1536T>A	p.Tyr512Ter	stop_gained	14/17	1		ENSP00000331063	A2
CDHR1	ENST00000372117.6	c.753T>A	p.Tyr251Ter	stop_gained	7/10	2		ENSP00000361189
CDHR1	ENST00000622973.1	c.270T>A	p.Tyr90Ter	stop_gained, NMD_transcript_variant	3/6	5		ENSP00000485151

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.52
GERP RS		-4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786205459; hg19: chr10-85971454;