rs75791347

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004933.3(CDH15):c.1750A>C(p.Lys584Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,535,124 control chromosomes in the GnomAD database, including 143,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13738 hom., cov: 33)

Exomes 𝑓: 0.43 ( 129538 hom. )

Consequence

CDH15
NM_004933.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.992

Publications

25 publications found

Variant links:

Genes affected

CDH15 (HGNC:1754): (cadherin 15) This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]

CDH15 Gene-Disease associations (from GenCC):

autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability, autosomal dominant 3
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
intellectual disability
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=6.49692E-6).

BP6

Variant 16-89192339-A-C is Benign according to our data. Variant chr16-89192339-A-C is described in ClinVar as Benign. ClinVar VariationId is 128646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH15	NM_004933.3 link	c.1750A>C	p.Lys584Gln	missense_variant	Exon 11 of 14	ENST00000289746.3	NP_004924.1	P55291

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH15	ENST00000289746.3 link	c.1750A>C	p.Lys584Gln	missense_variant	Exon 11 of 14	1	NM_004933.3	ENSP00000289746.2		P55291

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63857

AN:

151728

Hom.:

13710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.640

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.497

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.405

GnomAD2 exomes

AF:

0.434

AC:

57197

AN:

131770

AF XY:

0.438

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.615

Gnomad FIN exome

AF:

0.479

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.436

GnomAD4 exome

AF:

0.430

AC:

594134

AN:

1383280

Hom.:

129538

Cov.:

AF XY:

0.431

AC XY:

294390

AN XY:

682780

show subpopulations

African (AFR)

AF:

0.369

AC:

11661

AN:

31568

American (AMR)

AF:

0.369

AC:

13252

AN:

35884

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

8986

AN:

25024

East Asian (EAS)

AF:

0.649

AC:

23312

AN:

35908

South Asian (SAS)

AF:

0.496

AC:

39350

AN:

79348

European-Finnish (FIN)

AF:

0.478

AC:

16169

AN:

33846

Middle Eastern (MID)

AF:

0.425

AC:

2062

AN:

4854

European-Non Finnish (NFE)

AF:

0.421

AC:

454770

AN:

1079130

Other (OTH)

AF:

0.426

AC:

24572

AN:

57718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20391

40783

61174

81566

101957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14186

28372

42558

56744

70930

<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:

0.421

AC:

63922

AN:

151844

Hom.:

13738

Cov.:

AF XY:

0.426

AC XY:

31642

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.378

AC:

15650

AN:

41414

American (AMR)

AF:

0.388

AC:

5926

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1254

AN:

3470

East Asian (EAS)

AF:

0.640

AC:

3280

AN:

5128

South Asian (SAS)

AF:

0.492

AC:

2374

AN:

4824

European-Finnish (FIN)

AF:

0.497

AC:

5249

AN:

10570

Middle Eastern (MID)

AF:

0.394

AC:

115

AN:

292

European-Non Finnish (NFE)

AF:

0.426

AC:

28905

AN:

67858

Other (OTH)

AF:

0.411

AC:

866

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1908

3816

5725

7633

9541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.412

Hom.:

2392

Bravo

AF:

0.408

TwinsUK

AF:

0.421

AC:

1562

ALSPAC

AF:

0.418

AC:

1612

ESP6500AA

AF:

0.242

AC:

719

ESP6500EA

AF:

0.311

AC:

1977

ExAC

AF:

0.305

AC:

26540

Asia WGS

AF:

0.513

AC:

1782

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 24, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 3

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.9

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.035

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.13

MetaRNN

Benign

0.0000065

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.92

PhyloP100

-0.99

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.71

REVEL

Benign

0.023

Sift

Benign

0.46

Sift4G

Benign

0.57

Polyphen

0.0010

Vest4

0.15

MPC

0.032

ClinPred

0.00068

GERP RS

-4.4

Varity_R

0.053

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over