16-83748390-A-C

Position:

• chr16-83748390-A-C

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.1681+140A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 720,782 control chromosomes in the GnomAD database, including 750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 32)
  • Exomes 𝑓: 0.041 (624 hom.)
• Consequence: CDH13 NM_001257.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290

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]

CEDORA (HGNC:56653): (CDH13 antisense oligodendrocyte and neuron associated lncRNA)

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=-0.83).
• BP6: Variant 16-83748390-A-C is Benign according to our data. Variant chr16-83748390-A-C is described in ClinVar as [Benign]. Clinvar id is 1285859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5	c.1681+140A>C		intron_variant		ENST00000567109.6
CEDORA	XR_007065143.1	n.142-12472T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6	c.1681+140A>C		intron_variant		1	NM_001257.5	P1
CEDORA	ENST00000570056.2	n.142-19391T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5053 AN: 152216 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00764

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0411 AC: 23360 AN: 568448 Hom.: 624 AF XY: 0.0402 AC XY: 11867 AN XY: 295136

Gnomad4 AFR exome AF: 0.00722

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.0644

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0365

GnomAD4 genome AF: 0.0332 AC: 5051 AN: 152334 Hom.: 126 Cov.: 32 AF XY: 0.0346 AC XY: 2575 AN XY: 74488

Gnomad4 AFR AF: 0.00762

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0856

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0369 Hom.: 14

Bravo AF: 0.0299

Asia WGS AF: 0.0430 AC: 150 AN: 3478

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	-0.83
CADD	Benign	0.53
DANN	Benign	0.67

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: rs3743616; hg19: chr16-83781995; COSMIC: COSV51809761;