Genetic Variant CDHR5:p.Arg357Ser (chr11-619789-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021924.5(CDHR5):c.1071A>C(p.Arg357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,606,594 control chromosomes in the GnomAD database, including 324,052 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 27158 hom., cov: 35)

Exomes 𝑓: 0.64 ( 296894 hom. )

Consequence

CDHR5
NM_021924.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0960

Publications

55 publications found

Variant links:

Genes affected

CDHR5 (HGNC:7521): (cadherin related family member 5) This gene is a novel mucin-like gene that is a member of the cadherin superfamily. While encoding nonpolymorphic tandem repeats rich in proline, serine and threonine similar to mucin proteins, the gene also contains sequence encoding calcium-binding motifs found in all cadherins. The role of the hybrid extracellular region and the specific function of this protein have not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jan 2010]

CDHR5 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.6715473E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR5	NM_021924.5 link	c.1071A>C	p.Arg357Ser	missense_variant	Exon 10 of 15	ENST00000397542.7	NP_068743.3	Q9HBB8-1B4DV98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR5	ENST00000397542.7 link	c.1071A>C	p.Arg357Ser	missense_variant	Exon 10 of 15	1	NM_021924.5	ENSP00000380676.2		Q9HBB8-1

Frequencies

GnomAD3 genomes

AF:

0.591

AC:

89820

AN:

152036

Hom.:

27153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.703

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.677

Gnomad EAS

AF:

0.718

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.721

Gnomad MID

AF:

0.640

Gnomad NFE

AF:

0.640

Gnomad OTH

AF:

0.614

GnomAD2 exomes

AF:

0.627

AC:

146063

AN:

232808

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.707

Gnomad FIN exome

AF:

0.707

Gnomad NFE exome

AF:

0.644

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.637

AC:

926196

AN:

1454438

Hom.:

296894

Cov.:

AF XY:

0.641

AC XY:

463671

AN XY:

723566

show subpopulations

African (AFR)

AF:

0.447

AC:

14937

AN:

33434

American (AMR)

AF:

0.482

AC:

21340

AN:

44246

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

17750

AN:

26074

East Asian (EAS)

AF:

0.743

AC:

29421

AN:

39580

South Asian (SAS)

AF:

0.708

AC:

60884

AN:

85976

European-Finnish (FIN)

AF:

0.697

AC:

33908

AN:

48654

Middle Eastern (MID)

AF:

0.707

AC:

4072

AN:

5760

European-Non Finnish (NFE)

AF:

0.635

AC:

705249

AN:

1110550

Other (OTH)

AF:

0.642

AC:

38635

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

19524

39048

58571

78095

97619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18670

37340

56010

74680

93350

<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:

0.591

AC:

89851

AN:

152156

Hom.:

27158

Cov.:

AF XY:

0.597

AC XY:

44378

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.457

AC:

18993

AN:

41520

American (AMR)

AF:

0.531

AC:

8118

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

2351

AN:

3472

East Asian (EAS)

AF:

0.717

AC:

3703

AN:

5162

South Asian (SAS)

AF:

0.710

AC:

3431

AN:

4830

European-Finnish (FIN)

AF:

0.721

AC:

7644

AN:

10608

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.640

AC:

43488

AN:

67952

Other (OTH)

AF:

0.612

AC:

1292

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1942

3885

5827

7770

9712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.632

Hom.:

74039

Bravo

AF:

0.572

TwinsUK

AF:

0.636

AC:

2360

ALSPAC

AF:

0.631

AC:

2431

ESP6500AA

AF:

0.448

AC:

1971

ESP6500EA

AF:

0.623

AC:

5357

ExAC

AF:

0.625

AC:

75262

Asia WGS

AF:

0.660

AC:

2299

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.2

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0026

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00016

LIST_S2

Benign

0.13

T;.;T

MetaRNN

Benign

0.0000037

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.0

N;N;N

PhyloP100

0.096

PrimateAI

Uncertain

0.51

PROVEAN

Benign

2.5

N;N;N

REVEL

Benign

0.035

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.041

MutPred

0.46

Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);Loss of MoRF binding (P = 0.0231);

MPC

0.046

ClinPred

0.0017

GERP RS

2.0

Varity_R

0.084

gMVP

0.34

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over