rs543586963

Variant names:

• chr16-61655536-C-T
• rs543586963
• NM_001796.5:c.1840G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001796.5(CDH8):​c.1840G>A​(p.Val614Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CDH8 NM_001796.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

Genes affected

CDH8 (HGNC:1767): (cadherin 8) This gene encodes a type II classical cadherin from the cadherin superfamily, 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. The extracellular domain consists of 5 subdomains, each containing a cadherin motif, and appears to determine the specificity of the protein's homophilic cell adhesion activity. 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 in brain and is putatively involved in synaptic adhesion, axon outgrowth and guidance. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2635457).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001796.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH8	NM_001796.5	MANE Select	c.1840G>A	p.Val614Ile	missense	Exon 11 of 12	NP_001787.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH8	ENST00000577390.6	TSL:1 MANE Select	c.1840G>A	p.Val614Ile	missense	Exon 11 of 12	ENSP00000462701.1	P55286
	CDH8	ENST00000958085.1		c.1840G>A	p.Val614Ile	missense	Exon 11 of 12	ENSP00000628144.1
	CDH8	ENST00000299345.10	TSL:5	c.1840G>A	p.Val614Ile	missense	Exon 11 of 13	ENSP00000299345.6	X6R3Y6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111988

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	0.55	T
Polyphen		0.010	B
Vest4		0.39
MutPred		0.33		Gain of catalytic residue at P616 (P = 0.0332)
MVP		0.37
MPC		1.2
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.12
gMVP		0.34
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs543586963; hg19: chr16-61689440;