Variant 18-66529846-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021153.4(CDH19):c.1457A>G(p.Gln486Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000214 in 1,587,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

CDH19
NM_021153.4 missense, splice_region

Scores

Splicing: ADA: 0.6951

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.29

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33459353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH19	NM_021153.4 linkuse as main transcript	c.1457A>G	p.Gln486Arg	missense_variant, splice_region_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.1457A>G	p.Gln486Arg	missense_variant, splice_region_variant	9/12	1	NM_021153.4	ENSP00000262150	P1	Q9H159-1
CDH19	ENST00000579658.5 linkuse as main transcript	c.1457A>G	p.Gln486Arg	missense_variant, splice_region_variant, NMD_transcript_variant	9/12	1		ENSP00000463085
CDH19	ENST00000540086.5 linkuse as main transcript	c.1457A>G	p.Gln486Arg	missense_variant, splice_region_variant	9/10	2		ENSP00000439593		Q9H159-2

Frequencies

GnomAD3 genomes

AF:

0.0000993

AC:

AN:

150992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000364

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000501

AC:

AN:

239520

Hom.:

AF XY:

0.0000385

AC XY:

AN XY:

129838

show subpopulations

Gnomad AFR exome

AF:

0.000708

Gnomad AMR exome

AF:

0.0000317

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1436506

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

714994

show subpopulations

Gnomad4 AFR exome

AF:

0.000431

Gnomad4 AMR exome

AF:

0.0000236

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:

0.00000182

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000993

AC:

AN:

150992

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73540

show subpopulations

Gnomad4 AFR

AF:

0.000364

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

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

Mar 27, 2023

The c.1457A>G (p.Q486R) alteration is located in exon 9 (coding exon 8) of the CDH19 gene. This alteration results from a A to G substitution at nucleotide position 1457, causing the glutamine (Q) at amino acid position 486 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.026

T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.94

D;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.60

P;.

Vest4

0.50

MVP

0.70

MPC

0.096

ClinPred

0.24

GERP RS

5.5

Varity_R

0.46

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.70

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: -1

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