10-84194760-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033100.4(CDHR1):c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,519,356 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: CDHR1 NM_033100.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.416

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-84194760-C-T is Benign according to our data. Variant chr10-84194760-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-84194760-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0062 (944/152294) while in subpopulation AFR AF= 0.022 (915/41582). AF 95% confidence interval is 0.0208. There are 12 homozygotes in gnomad4. There are 423 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR1	NM_033100.4	c.-1C>T		5_prime_UTR_variant	1/17	ENST00000623527.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR1	ENST00000623527.4	c.-1C>T		5_prime_UTR_variant	1/17	1	NM_033100.4	P2
CDHR1	ENST00000332904.7	c.-1C>T		5_prime_UTR_variant	1/17	1		A2

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 944 AN: 152184 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.000909 AC: 106 AN: 116578 Hom.: 2 AF XY: 0.000653 AC XY: 42 AN XY: 64326

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.000556

GnomAD4 exome AF: 0.000617 AC: 843 AN: 1367062 Hom.: 11 Cov.: 31 AF XY: 0.000494 AC XY: 333 AN XY: 674318

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.000665

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000385

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000373

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152294 Hom.: 12 Cov.: 33 AF XY: 0.00568 AC XY: 423 AN XY: 74472

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00672

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 05, 2015

- -

Cone-rod dystrophy 15 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.88

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

LitVar

Other links and lift over

dbSNP: rs114273269; hg19: chr10-85954516;