18-66505261-G-T

Position:

• chr18-66505261-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021153.4(CDH19):​c.1870C>A​(p.Gln624Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,433,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CDH19 NM_021153.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.188

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04907027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH19	NM_021153.4	c.1870C>A	p.Gln624Lys	missense_variant	12/12	ENST00000262150.7	NP_066976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH19	ENST00000262150.7	c.1870C>A	p.Gln624Lys	missense_variant	12/12	1	NM_021153.4	ENSP00000262150.2
CDH19	ENST00000579658.5	n.*216C>A		non_coding_transcript_exon_variant	12/12	1		ENSP00000463085.1
CDH19	ENST00000579658.5	n.*216C>A		3_prime_UTR_variant	12/12	1		ENSP00000463085.1
CDH19	ENST00000540086	c.*27C>A		3_prime_UTR_variant	10/10	2		ENSP00000439593.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1433630 Hom.: 0 Cov.: 30 AF XY: 0.00000421 AC XY: 3 AN XY: 712760

Gnomad4 AFR exome AF: 0.00

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: 0.00000544

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.1870C>A (p.Q624K) alteration is located in exon 12 (coding exon 11) of the CDH19 gene. This alteration results from a C to A substitution at nucleotide position 1870, causing the glutamine (Q) at amino acid position 624 to be replaced by a lysine (K). 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	0.066
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.6
DANN	Benign	0.55
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.84	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.13
Sift	Benign	0.67	T
Sift4G	Benign	0.25	T
Polyphen		0.0090	B
Vest4		0.046
MutPred		0.54		Gain of methylation at Q624 (P = 0.0106);
MVP		0.72
MPC		0.043
ClinPred		0.056	T
GERP RS		3.3
Varity_R		0.053
gMVP		0.17

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

Other links and lift over

dbSNP: rs1279677840; hg19: chr18-64172498;