rs74145715

Variant names:

• chr10-84200648-G-C
• rs74145715
• NM_033100.4:c.486G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033100.4(CDHR1):​c.486G>C​(p.Arg162Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,612,546 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (158 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (180 hom.)
• Consequence: CDHR1 NM_033100.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56
• Publications: 3 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00458923).
• BP6: Variant 10-84200648-G-C is Benign according to our data. Variant chr10-84200648-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0858 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	NM_033100.4	MANE Select	c.486G>C	p.Arg162Ser	missense	Exon 6 of 17	NP_149091.1
	CDHR1	NM_001171971.3		c.486G>C	p.Arg162Ser	missense	Exon 6 of 17	NP_001165442.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDHR1	ENST00000623527.4	TSL:1 MANE Select	c.486G>C	p.Arg162Ser	missense	Exon 6 of 17	ENSP00000485478.1
	CDHR1	ENST00000332904.7	TSL:1	c.486G>C	p.Arg162Ser	missense	Exon 6 of 17	ENSP00000331063.3

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3925 AN: 152126 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00679 AC: 1680 AN: 247330 AF XY: 0.00486

Gnomad AFR exome AF: 0.0892

Gnomad AMR exome AF: 0.00525

Gnomad ASJ exome AF: 0.000903

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00304 AC: 4443 AN: 1460302 Hom.: 180 Cov.: 32 AF XY: 0.00268 AC XY: 1949 AN XY: 726242

African (AFR) AF: 0.0955 AC: 3195 AN: 33446

American (AMR) AF: 0.00617 AC: 275 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000280 AC: 24 AN: 85686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5762

European-Non Finnish (NFE) AF: 0.000333 AC: 370 AN: 1111384

Other (OTH) AF: 0.00802 AC: 484 AN: 60362

GnomAD4 genome AF: 0.0258 AC: 3934 AN: 152244 Hom.: 158 Cov.: 32 AF XY: 0.0247 AC XY: 1838 AN XY: 74454

African (AFR) AF: 0.0881 AC: 3659 AN: 41516

American (AMR) AF: 0.0105 AC: 160 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68004

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.00433 Hom.: 14

Bravo AF: 0.0289

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0906 AC: 399

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00818 AC: 993

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N
PhyloP100		1.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.051
Sift	Benign	0.096	T
Sift4G	Benign	0.12	T
Polyphen		0.025	B
Vest4		0.23
MutPred		0.54		Gain of glycosylation at R162 (P = 0.0326)
MVP		0.20
ClinPred		0.0042	T
GERP RS		2.4
Varity_R		0.099
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74145715; hg19: chr10-85960404;