Genetic Variant CDHR1:p.Val80Val (chr10-84196593-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_033100.4(CDHR1):c.240C>T(p.Val80Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,242 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V80V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 9 hom., cov: 32)

Exomes 𝑓: 0.013 ( 140 hom. )

Consequence

CDHR1
NM_033100.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.34

Publications

2 publications found

Variant links:

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]

CDHR1 Gene-Disease associations (from GenCC):

cone-rod dystrophy 15
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
retinitis pigmentosa 65
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CDHR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 10-84196593-C-T is Benign according to our data. Variant chr10-84196593-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262212.

BP7

Synonymous conserved (PhyloP=2.34 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00931 (1419/152356) while in subpopulation NFE AF = 0.0153 (1038/68040). AF 95% confidence interval is 0.0145. There are 9 homozygotes in GnomAd4. There are 646 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	NM_033100.4	MANE Select	c.240C>T	p.Val80Val	synonymous	Exon 3 of 17	NP_149091.1	Q96JP9-1
	CDHR1	NM_001171971.3		c.240C>T	p.Val80Val	synonymous	Exon 3 of 17	NP_001165442.1	Q96JP9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDHR1	ENST00000623527.4	TSL:1 MANE Select	c.240C>T	p.Val80Val	synonymous	Exon 3 of 17	ENSP00000485478.1	Q96JP9-1
CDHR1	ENST00000332904.7	TSL:1	c.240C>T	p.Val80Val	synonymous	Exon 3 of 17	ENSP00000331063.3	Q96JP9-2
CDHR1	ENST00000926454.1		c.240C>T	p.Val80Val	synonymous	Exon 3 of 16	ENSP00000596513.1

Frequencies

GnomAD3 genomes

AF:

0.00931

AC:

1418

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00974

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00936

AC:

2354

AN:

251496

AF XY:

0.00955

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00838

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0132

AC:

19228

AN:

1461886

Hom.:

140

Cov.:

AF XY:

0.0127

AC XY:

9265

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

33480

American (AMR)

AF:

0.00883

AC:

395

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

497

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00291

AC:

251

AN:

86258

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5768

European-Non Finnish (NFE)

AF:

0.0153

AC:

17056

AN:

1112004

Other (OTH)

AF:

0.0122

AC:

736

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1098

2195

3293

4390

5488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00931

AC:

1419

AN:

152356

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

646

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41576

American (AMR)

AF:

0.00973

AC:

149

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1038

AN:

68040

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.00968

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0166

EpiControl

AF:

0.0179

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cone-Rod Dystrophy, Recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.5

(source)

DANN

Benign

0.78

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over