16-83794883-A-G

Position:

• chr16-83794883-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001257.5(CDH13):​c.2135-140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 659,134 control chromosomes in the GnomAD database, including 2,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (484 hom., cov: 31)
  • Exomes 𝑓: 0.091 (2219 hom.)
• Consequence: CDH13 NM_001257.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.545

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]

CDH13-AS2 (HGNC:56243): (CDH13 antisense RNA 2)

HSBP1 (HGNC:5203): (heat shock factor binding protein 1) The heat-shock response is elicited by exposure of cells to thermal and chemical stress and through the activation of HSFs (heat shock factors) results in the elevated expression of heat-shock induced genes. Heat shock factor binding protein 1 (HSBP1), is a 76-amino-acid protein that binds to heat shock factor 1(HSF1), which is a transcription factor involved in the HS response. During HS response, HSF1 undergoes conformational transition from an inert non-DNA-binding monomer to active functional trimers. HSBP1 is nuclear-localized and interacts with the active trimeric state of HSF1 to negatively regulate HSF1 DNA-binding activity. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. When overexpressed in C.elegans HSBP1 has severe effects on survival of the animals after thermal and chemical stress consistent with a role of HSBP1 as a negative regulator of heat shock response. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-83794883-A-G is Benign according to our data. Variant chr16-83794883-A-G is described in ClinVar as [Benign]. Clinvar id is 1250972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH13	NM_001257.5	c.2135-140A>G		intron_variant		ENST00000567109.6	NP_001248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH13	ENST00000567109.6	c.2135-140A>G		intron_variant		1	NM_001257.5	ENSP00000479395	P1
CDH13-AS2	ENST00000565714.5	n.95-4679T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 10606 AN: 139978 Hom.: 483 Cov.: 31

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.0653

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.0624

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0705

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0758

GnomAD4 exome AF: 0.0914 AC: 47418 AN: 519056 Hom.: 2219 AF XY: 0.0924 AC XY: 25703 AN XY: 278120

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0725

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0703

Gnomad4 OTH exome AF: 0.0826

GnomAD4 genome AF: 0.0757 AC: 10605 AN: 140078 Hom.: 484 Cov.: 31 AF XY: 0.0810 AC XY: 5547 AN XY: 68510

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0847

Gnomad4 ASJ AF: 0.0624

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.0653

Gnomad4 OTH AF: 0.0770

Alfa AF: 0.0619 Hom.: 49

Bravo AF: 0.0657

Asia WGS AF: 0.111 AC: 385 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.099
DANN	Benign	0.39

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: rs74786055; hg19: chr16-83828488;