NM_033100.4:c.1A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_StrongPP5

The NM_033100.4(CDHR1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,519,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CDHR1
NM_033100.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 2.51

Publications

4 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 39 codons. Genomic position: 84195553. Lost 0.045 part of the original CDS.

PP5

Variant 10-84194761-A-G is Pathogenic according to our data. Variant chr10-84194761-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193474.

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.1A>G	p.Met1?	start_lost	Exon 1 of 17	NP_149091.1	Q96JP9-1
	CDHR1	NM_001171971.3		c.1A>G	p.Met1?	start_lost	Exon 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000485478.1	Q96JP9-1
CDHR1	ENST00000332904.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000331063.3	Q96JP9-2
CDHR1	ENST00000926454.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000596513.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

116880

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000464

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000271

AC:

AN:

1367378

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

674492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29308

American (AMR)

AF:

0.00

AC:

AN:

34638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24508

East Asian (EAS)

AF:

0.00

AC:

AN:

34228

South Asian (SAS)

AF:

0.00

AC:

AN:

78006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4020

European-Non Finnish (NFE)

AF:

0.0000345

AC:

AN:

1072322

Other (OTH)

AF:

0.00

AC:

AN:

56974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68008

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CDHR1-related disorder (1)

Cone-rod dystrophy 15 (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.069

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.94

PhyloP100

2.5

PROVEAN

Benign

-0.47

REVEL

Benign

0.23

Sift

Uncertain

0.026

Sift4G

Pathogenic

0.0

Polyphen

0.028

Vest4

0.78

MutPred

0.95

Loss of catalytic residue at M1 (P = 0.0029)

MVP

0.35

ClinPred

0.72

GERP RS

2.8

PromoterAI

-0.054

Neutral

(source)

Varity_R

0.45

gMVP

0.60

Mutation Taster

=9/191

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over