Variant 18-66529945-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021153.4(CDH19):c.1358C>T(p.Ser453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,541,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

CDH19
NM_021153.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

CDH19 (HGNC:1758): (cadherin 19) This gene is one of three related type II cadherin genes situated in a cluster on chromosome 18. The encoded protein is a calcium dependent cell-cell adhesion glycoprotein containing five extracellular cadherin repeats. Loss of cadherins may be associated with cancer formation. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Aug 2012]

CDH19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH19	NM_021153.4 linkuse as main transcript	c.1358C>T	p.Ser453Leu	missense_variant	9/12	ENST00000262150.7	NP_066976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH19	ENST00000262150.7 linkuse as main transcript	c.1358C>T	p.Ser453Leu	missense_variant	9/12	1	NM_021153.4	ENSP00000262150	P1	Q9H159-1
CDH19	ENST00000579658.5 linkuse as main transcript	c.1358C>T	p.Ser453Leu	missense_variant, NMD_transcript_variant	9/12	1		ENSP00000463085
CDH19	ENST00000540086.5 linkuse as main transcript	c.1358C>T	p.Ser453Leu	missense_variant	9/10	2		ENSP00000439593		Q9H159-2

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151450

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000630

AC:

AN:

238240

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

129134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000741

AC:

103

AN:

1390548

Hom.:

Cov.:

AF XY:

0.0000648

AC XY:

AN XY:

694546

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000936

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151450

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73908

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000968

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The c.1358C>T (p.S453L) alteration is located in exon 9 (coding exon 8) of the CDH19 gene. This alteration results from a C to T substitution at nucleotide position 1358, causing the serine (S) at amino acid position 453 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.5

N;D

REVEL

Benign

0.057

Sift

Uncertain

0.024

D;D

Sift4G

Benign

0.067

T;T

Polyphen

0.041

B;.

Vest4

0.32

MVP

0.47

MPC

0.039

ClinPred

0.50

GERP RS

3.5

Varity_R

0.19

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: 21

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