chr10-84194773-C-T

Variant names:

• chr10-84194773-C-T
• rs766698407
• NM_033100.4:c.13C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033100.4(CDHR1):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000808 in 1,522,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: CDHR1 NM_033100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07806283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR1	NM_033100.4	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 17	1	NM_033100.4	ENSP00000485478.1
CDHR1	ENST00000332904.7	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 17	1		ENSP00000331063.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000883 AC: 121 AN: 1370658 Hom.: 0 Cov.: 31 AF XY: 0.0000932 AC XY: 63 AN XY: 676058

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: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000587 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the CDHR1 protein (p.Arg5Trp). This variant is present in population databases (rs766698407, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDHR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1473113). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.67	.;N
REVEL	Benign	0.080
Sift	Benign	0.051	.;T
Sift4G	Uncertain	0.045	D;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.54		Loss of disorder (P = 0.0056);Loss of disorder (P = 0.0056);
MVP		0.092
ClinPred		0.21	T
GERP RS		2.1
Varity_R		0.041
gMVP		0.26

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: rs766698407; hg19: chr10-85954529;