5-26881188-C-A

Position:

• chr5-26881188-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016279.4(CDH9):​c.2318G>T​(p.Arg773Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH9 NM_016279.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

Genes affected

CDH9 (HGNC:1768): (cadherin 9) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH9	NM_016279.4	c.2318G>T	p.Arg773Leu	missense_variant	12/12	ENST00000231021.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH9	ENST00000231021.9	c.2318G>T	p.Arg773Leu	missense_variant	12/12	1	NM_016279.4	P1
CDH9	ENST00000505020.1	n.1334G>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 17, 2023

The c.2318G>T (p.R773L) alteration is located in exon 12 (coding exon 11) of the CDH9 gene. This alteration results from a G to T substitution at nucleotide position 2318, causing the arginine (R) at amino acid position 773 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.71
Sift	Benign	0.080	T
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.57
MutPred		0.87		Gain of ubiquitination at K775 (P = 0.0418);
MVP		0.82
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.78

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: rs553402369; hg19: chr5-26881297;