16-83032046-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001257.5(CDH13):c.194G>A(p.Arg65His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,606,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CDH13 NM_001257.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00200

Genes affected

CDH13 (HGNC:1753): (cadherin 13) This gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The gene is hypermethylated in many types of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13873222).
• BP6: Variant 16-83032046-G-A is Benign according to our data. Variant chr16-83032046-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2514684.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5	c.194G>A	p.Arg65His	missense_variant	3/14	ENST00000567109.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6	c.194G>A	p.Arg65His	missense_variant	3/14	1	NM_001257.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000423 AC: 10 AN: 236678 Hom.: 0 AF XY: 0.0000313 AC XY: 4 AN XY: 127944

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000467

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000105 AC: 152 AN: 1454014 Hom.: 0 Cov.: 29 AF XY: 0.000104 AC XY: 75 AN XY: 722392

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.068	T;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N;.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.14
MVP		0.69
MPC		0.089
ClinPred		0.041	T
GERP RS		-0.11
Varity_R		0.026
gMVP		0.25

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: rs371659407; hg19: chr16-83065651; COSMIC: COSV51786052;