18-66509048-C-G

Position:

• chr18-66509048-C-G

Variant summary

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

The NM_021153.4(CDH19):​c.1775G>C​(p.Gly592Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH19 NM_021153.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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]

ACMG classification

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	c.1775G>C	p.Gly592Ala	missense_variant	11/12	ENST00000262150.7	NP_066976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH19	ENST00000262150.7	c.1775G>C	p.Gly592Ala	missense_variant	11/12	1	NM_021153.4	ENSP00000262150	P1
CDH19	ENST00000579658.5	c.*121G>C		3_prime_UTR_variant, NMD_transcript_variant	11/12	1		ENSP00000463085
CDH19	ENST00000540086.5	c.1459-3746G>C		intron_variant		2		ENSP00000439593

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 31, 2022

The c.1775G>C (p.G592A) alteration is located in exon 11 (coding exon 10) of the CDH19 gene. This alteration results from a G to C substitution at nucleotide position 1775, causing the glycine (G) at amino acid position 592 to be replaced by an alanine (A). 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	0.094
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.029	D
Polyphen		0.97	D
Vest4		0.17
MutPred		0.69		Gain of catalytic residue at G592 (P = 0.0414);
MVP		0.68
MPC		0.041
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.29
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-64176285;