16-61727125-G-C

Variant names:

• chr16-61727125-G-C
• rs1444313183
• NM_001796.5:c.1505C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001796.5(CDH8):​c.1505C>G​(p.Ala502Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH8 NM_001796.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26546115).

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.1505C>G	p.Ala502Gly	missense	Exon 9 of 12	NP_001787.2
	CDH8	NM_001410893.1		c.1505C>G	p.Ala502Gly	missense	Exon 9 of 9	NP_001397822.1	J3QLE6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH8	ENST00000577390.6	TSL:1 MANE Select	c.1505C>G	p.Ala502Gly	missense	Exon 9 of 12	ENSP00000462701.1	P55286
	CDH8	ENST00000958085.1		c.1505C>G	p.Ala502Gly	missense	Exon 9 of 12	ENSP00000628144.1
	CDH8	ENST00000299345.10	TSL:5	c.1505C>G	p.Ala502Gly	missense	Exon 9 of 13	ENSP00000299345.6	X6R3Y6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249840 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459452 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726060

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.0000224 AC: 1 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110416

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

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	0.22
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.086	T
Polyphen		0.022	B
Vest4		0.66
MutPred		0.52		Loss of stability (P = 0.032)
MVP		0.42
MPC		1.1
ClinPred		0.56	D
GERP RS		5.8
Varity_R		0.31
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

Other links and lift over

dbSNP: rs1444313183; hg19: chr16-61761029;