5-19473351-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004934.5(CDH18):c.2248A>G(p.Ile750Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CDH18 NM_004934.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

CDH18 (HGNC:1757): (cadherin 18) This gene encodes a type II classical cadherin from the cadherin superfamily of integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. This particular cadherin is expressed specifically in the central nervous system and is putatively involved in synaptic adhesion, axon outgrowth and guidance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18782914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH18	NM_004934.5	c.2248A>G	p.Ile750Val	missense_variant	13/13	ENST00000382275.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH18	ENST00000382275.6	c.2248A>G	p.Ile750Val	missense_variant	13/13	1	NM_004934.5	P1
CDH18	ENST00000274170.8	c.2248A>G	p.Ile750Val	missense_variant	11/11	1		P1
CDH18	ENST00000507958.5	c.2248A>G	p.Ile750Val	missense_variant	15/15	2		P1
CDH18	ENST00000510297.1	n.499A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.0000319 AC: 8 AN: 250946 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135606

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461690 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74324

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00196

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

Bravo AF: 0.000487

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

May 10, 2022

The c.2248A>G (p.I750V) alteration is located in exon 13 (coding exon 11) of the CDH18 gene. This alteration results from a A to G substitution at nucleotide position 2248, causing the isoleucine (I) at amino acid position 750 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.0080	B;B;B
Vest4		0.18
MutPred		0.82		Loss of glycosylation at S749 (P = 0.1013);Loss of glycosylation at S749 (P = 0.1013);Loss of glycosylation at S749 (P = 0.1013);
MVP		0.83
MPC		0.10
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.18
gMVP		0.32

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: rs757108674; hg19: chr5-19473460;