rs35549391

Positions:

• chr16-83670814-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001257.5(CDH13):​c.1126G>A​(p.Ala376Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,613,924 control chromosomes in the GnomAD database, including 45 homozygotes. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (44 hom.)
• Consequence: CDH13 NM_001257.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.42

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]

LOC124900603 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007640034).
• BP6: Variant 16-83670814-G-A is Benign according to our data. Variant chr16-83670814-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 44 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5	c.1126G>A	p.Ala376Thr	missense_variant	9/14	ENST00000567109.6
LOC124900603	XR_001752385.3	n.3529-3223C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6	c.1126G>A	p.Ala376Thr	missense_variant	9/14	1	NM_001257.5	P1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00836

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00563 AC: 1404 AN: 249164 Hom.: 7 AF XY: 0.00581 AC XY: 785 AN XY: 135154

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00237

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00727

GnomAD4 exome AF: 0.00709 AC: 10360 AN: 1461596 Hom.: 44 Cov.: 31 AF XY: 0.00707 AC XY: 5140 AN XY: 727090

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.00805

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.00505 AC: 770 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00452 AC XY: 337 AN XY: 74494

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00836

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00826 Hom.: 7

Bravo AF: 0.00498

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00154 AC: 6

ESP6500EA AF: 0.00700 AC: 58

ExAC AF: 0.00592 AC: 715

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00777

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	.;N;N
REVEL	Benign	0.093
Sift	Benign	0.18	.;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.27	B;.;.
Vest4		0.18
MVP		0.80
MPC		0.075
ClinPred		0.017	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.44

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: rs35549391; hg19: chr16-83704419; COSMIC: COSV99075384;