16-89179482-G-T

Variant names:

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.109G>T(p.Ala37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,476 control chromosomes in the GnomAD database, including 10,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A37V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.076 ( 974 hom., cov: 33)

Exomes 𝑓: 0.083 ( 9861 hom. )

Consequence

CDH15
NM_004933.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.371

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 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=8.969605E-4).

BP6

Variant 16-89179482-G-T is Benign according to our data. Variant chr16-89179482-G-T is described in ClinVar as [Benign]. Clinvar id is 128642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH15	NM_004933.3 link	c.109G>T	p.Ala37Ser	missense_variant	Exon 2 of 14	ENST00000289746.3	NP_004924.1	P55291

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH15	ENST00000289746.3 link	c.109G>T	p.Ala37Ser	missense_variant	Exon 2 of 14	1	NM_004933.3	ENSP00000289746.2	P55291
CDH15	ENST00000521087.5 link	n.174G>T		non_coding_transcript_exon_variant	Exon 2 of 3	5
CDH15	ENST00000524089.1 link	n.174G>T		non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0764

AC:

11623

AN:

152192

Hom.:

968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0620

Gnomad ASJ

AF:

0.0613

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.0458

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.0608

Gnomad OTH

AF:

0.0903

GnomAD2 exomes

AF:

0.111

AC:

27725

AN:

250236

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.0616

Gnomad ASJ exome

AF:

0.0655

Gnomad EAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0620

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0825

AC:

120607

AN:

1461166

Hom.:

9861

Cov.:

AF XY:

0.0881

AC XY:

64054

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.0464

AC:

1554

AN:

33478

Gnomad4 AMR exome

AF:

0.0624

AC:

2790

AN:

44708

Gnomad4 ASJ exome

AF:

0.0648

AC:

1693

AN:

26112

Gnomad4 EAS exome

AF:

0.454

AC:

18010

AN:

39696

Gnomad4 SAS exome

AF:

0.258

AC:

22272

AN:

86254

Gnomad4 FIN exome

AF:

0.0443

AC:

2343

AN:

52902

Gnomad4 NFE exome

AF:

0.0585

AC:

65050

AN:

1111874

Gnomad4 Remaining exome

AF:

0.0985

AC:

5950

AN:

60378

Heterozygous variant carriers

5770

11540

17309

23079

28849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

2698

5396

8094

10792

13490

<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:

0.0764

AC:

11640

AN:

152310

Hom.:

974

Cov.:

AF XY:

0.0806

AC XY:

6002

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0482

AC:

0.048218

AN:

0.048218

Gnomad4 AMR

AF:

0.0621

AC:

0.0620672

AN:

0.0620672

Gnomad4 ASJ

AF:

0.0613

AC:

0.0613479

AN:

0.0613479

Gnomad4 EAS

AF:

0.447

AC:

0.446981

AN:

0.446981

Gnomad4 SAS

AF:

0.261

AC:

0.260978

AN:

0.260978

Gnomad4 FIN

AF:

0.0458

AC:

0.0458137

AN:

0.0458137

Gnomad4 NFE

AF:

0.0608

AC:

0.0608364

AN:

0.0608364

Gnomad4 OTH

AF:

0.0992

AC:

0.0992439

AN:

0.0992439

Heterozygous variant carriers

506

1011

1517

2022

2528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0623

Hom.:

140

Bravo

AF:

0.0742

TwinsUK

AF:

0.0588

AC:

218

ALSPAC

AF:

0.0597

AC:

230

ESP6500AA

AF:

0.0505

AC:

222

ESP6500EA

AF:

0.0631

AC:

543

ExAC

AF:

0.113

AC:

13652

Asia WGS

AF:

0.316

AC:

1099

AN:

3478

EpiCase

AF:

0.0671

EpiControl

AF:

0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 27, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.5

DANN

Benign

0.36

DEOGEN2

Benign

0.041

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.41

MetaRNN

Benign

0.00090

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.29

REVEL

Benign

0.026

Sift

Benign

0.94

Sift4G

Benign

0.48

Polyphen

0.0060

Vest4

0.092

MPC

0.032

ClinPred

0.0065

GERP RS

-9.2

Varity_R

0.035

gMVP

0.36

Mutation Taster

=95/5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over