chr16-82639464-A-G

Variant names:

Variant summary

Our verdict is The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PP3BS2BP6

The NM_001220488.2(CDH13):c.185A>G (p.Gln62Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. Note: NM_001220488.2 is not a MANE Select or MANE Plus Clinical transcript for CDH13; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.000735 (AC=1,125) in the gnomAD database across 1,530,588 control chromosomes, including 6 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.012. In-silico predictor (REVEL) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 5 hom. )

Consequence

CDH13
NM_001220488.2 missense, splice_region

Scores

Splicing: ADA: 0.0001373

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.563

Publications

1 publications found

Variant links:

Genes affected

CDH13 (HGNC:1753): (cadherin 13) This gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The gene is hypermethylated in many types of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2011]

CDH13 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001220488.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 points.

PP3

Splicing predictors (SpliceAI/dbscSNV) support splicing impact — supporting computational evidence (PP3); Splicing verdict: pathogenic (Supporting).; Germline computational verdict: not pathogenic.

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 6.; Very high cumulative gnomAD AC = 1125 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001220488.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH13	NM_001257.5	MANE Select	c.45+12327A>G		intron	N/A	NP_001248.1	P55290-1
CDH13	NM_001220488.2		c.185A>G	p.Gln62Arg	missense splice_region	Exon 2 of 15	NP_001207417.1	P55290-4
CDH13	NM_001220489.2		c.45+12327A>G		intron	N/A	NP_001207418.1	P55290-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDH13	ENST00000567109.6	TSL:1 MANE Select	c.45+12327A>G	intron	N/A	ENSP00000479395.1	P55290-1
CDH13	ENST00000431540.7	TSL:1	c.45+12327A>G	intron	N/A	ENSP00000408632.3	P55290-2
CDH13	ENST00000567445.1	TSL:1	c.45+12327A>G	intron	N/A	ENSP00000456297.1	H3BRL7

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

568

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000977

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:

0.000153

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.000900

AC:

115

AN:

128370

AF XY:

0.000839

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.000397

AC:

556

AN:

1378266

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

234

AN XY:

680448

show subpopulations

African (AFR)

AF:

0.0125

AC:

393

AN:

31522

American (AMR)

AF:

0.000565

AC:

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35700

South Asian (SAS)

AF:

0.00

AC:

AN:

79126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33464

Middle Eastern (MID)

AF:

0.000534

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000763

AC:

AN:

1074178

Other (OTH)

AF:

0.000931

AC:

AN:

57752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00374

AC:

569

AN:

152322

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0129

AC:

536

AN:

41570

American (AMR)

AF:

0.000977

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000153

AC:

AN:

68032

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.00421

Asia WGS

AF:

0.000290

AC:

AN:

3478

Local populations

ABraOM SABE-WGS-1171

AF:

0.00470

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDH13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.54

(source)

DANN

Benign

0.85

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.17

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.1

PhyloP100

-0.56

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.79

REVEL

Benign

0.016

Sift

Benign

0.044

Sift4G

Benign

0.061

gMVP

0.31

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.64

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over