rs2306907

Variant names:

• chr16-83486473-G-A
• rs2306907
• NM_001257.5:c.782-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001257.5(CDH13):​c.782-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,609,752 control chromosomes in the GnomAD database, including 42,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3566 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39142 hom.)
• Consequence: CDH13 NM_001257.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001922
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.16
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-83486473-G-A is Benign according to our data. Variant chr16-83486473-G-A is described in ClinVar as Benign. ClinVar VariationId is 257650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH13	NM_001257.5	c.782-4G>A		splice_region_variant, intron_variant	Intron 6 of 13	ENST00000567109.6	NP_001248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH13	ENST00000567109.6	c.782-4G>A		splice_region_variant, intron_variant	Intron 6 of 13	1	NM_001257.5	ENSP00000479395.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32424 AN: 151952 Hom.: 3565 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.229 AC: 56678 AN: 247390 AF XY: 0.224

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.227 AC: 330603 AN: 1457682 Hom.: 39142 Cov.: 32 AF XY: 0.225 AC XY: 162797 AN XY: 724752

African (AFR) AF: 0.154 AC: 5152 AN: 33432

American (AMR) AF: 0.331 AC: 14764 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6133 AN: 26032

East Asian (EAS) AF: 0.105 AC: 4169 AN: 39620

South Asian (SAS) AF: 0.146 AC: 12588 AN: 85996

European-Finnish (FIN) AF: 0.243 AC: 12813 AN: 52786

Middle Eastern (MID) AF: 0.291 AC: 1659 AN: 5708

European-Non Finnish (NFE) AF: 0.235 AC: 260290 AN: 1109234

Other (OTH) AF: 0.216 AC: 13035 AN: 60248

GnomAD4 genome AF: 0.213 AC: 32436 AN: 152070 Hom.: 3566 Cov.: 32 AF XY: 0.213 AC XY: 15829 AN XY: 74294

African (AFR) AF: 0.154 AC: 6394 AN: 41486

American (AMR) AF: 0.284 AC: 4334 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 806 AN: 3466

East Asian (EAS) AF: 0.111 AC: 575 AN: 5160

South Asian (SAS) AF: 0.147 AC: 707 AN: 4808

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10572

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16341 AN: 67976

Other (OTH) AF: 0.257 AC: 543 AN: 2116

Alfa AF: 0.235 Hom.: 8866

Bravo AF: 0.219

EpiCase AF: 0.254

EpiControl AF: 0.245

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.031
DANN	Benign	0.71
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0020
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: rs2306907; hg19: chr16-83520078; COSMIC: COSV51792102;