5-19591065-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_004934.5(CDH18):c.991T>C(p.Leu331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,573,662 control chromosomes in the GnomAD database, including 26,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (2024 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24515 hom.)
• Consequence: CDH18 NM_004934.5 synonymous
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.45

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH18	NM_004934.5	c.991T>C	p.Leu331=	synonymous_variant	7/13	ENST00000382275.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH18	ENST00000382275.6	c.991T>C	p.Leu331=	synonymous_variant	7/13	1	NM_004934.5	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21892 AN: 151954 Hom.: 2022 Cov.: 32

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.170 AC: 38961 AN: 229386 Hom.: 3974 AF XY: 0.171 AC XY: 21335 AN XY: 124566

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.000882

Gnomad SAS exome AF: 0.168

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.179 AC: 253792 AN: 1421590 Hom.: 24515 Cov.: 27 AF XY: 0.179 AC XY: 126534 AN XY: 707358

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.000516

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.144 AC: 21884 AN: 152072 Hom.: 2024 Cov.: 32 AF XY: 0.146 AC XY: 10868 AN XY: 74324

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.139

Alfa AF: 0.169 Hom.: 1605

Bravo AF: 0.137

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Childhood apraxia of speech Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Apr 27, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.1
Dann	Benign	0.84

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: rs17285716; hg19: chr5-19591174; COSMIC: COSV56910537;