10-84194767-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033100.4(CDHR1):c.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CDHR1 NM_033100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.197

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR1	NM_033100.4	c.7C>T	p.Arg3Cys	missense_variant	1/17	ENST00000623527.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR1	ENST00000623527.4	c.7C>T	p.Arg3Cys	missense_variant	1/17	1	NM_033100.4	P2
CDHR1	ENST00000332904.7	c.7C>T	p.Arg3Cys	missense_variant	1/17	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 675312

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDHR1 protein function. This variant has not been reported in the literature in individuals affected with CDHR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3 of the CDHR1 protein (p.Arg3Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.0020	B;B
Vest4		0.20
MutPred		0.68		Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);
MVP		0.21
ClinPred		0.59	D
GERP RS		0.86
Varity_R		0.14
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1841996352; hg19: chr10-85954523;