10-84194789-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033100.4(CDHR1):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000686 in 1,531,590 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 (★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: CDHR1 NM_033100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.182

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048463732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDHR1	NM_033100.4	c.29C>T	p.Ala10Val	missense_variant	1/17	ENST00000623527.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDHR1	ENST00000623527.4	c.29C>T	p.Ala10Val	missense_variant	1/17	1	NM_033100.4	P2
CDHR1	ENST00000332904.7	c.29C>T	p.Ala10Val	missense_variant	1/17	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000942 AC: 12 AN: 127390 Hom.: 0 AF XY: 0.0000718 AC XY: 5 AN XY: 69662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000165

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: 0.000149

Gnomad OTH exome AF: 0.000252

GnomAD4 exome AF: 0.0000710 AC: 98 AN: 1379412 Hom.: 0 Cov.: 31 AF XY: 0.0000793 AC XY: 54 AN XY: 680666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000197

Gnomad4 ASJ exome AF: 0.0000799

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000715

Gnomad4 OTH exome AF: 0.000208

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

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

Aug 31, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the CDHR1 protein (p.Ala10Val). This variant is present in population databases (rs750454492, gnomAD 0.02%). 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: 1465268). 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	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.18
ClinPred		0.065	T
GERP RS		1.1
Varity_R		0.024
gMVP		0.18

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: rs750454492; hg19: chr10-85954545;