16-83747999-T-C

Position:

• chr16-83747999-T-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.1539-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,152,732 control chromosomes in the GnomAD database, including 79,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10035 hom., cov: 30)
  • Exomes 𝑓: 0.37 (69181 hom.)
• Consequence: CDH13 NM_001257.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0220

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=-0.85).
• BP6: Variant 16-83747999-T-C is Benign according to our data. Variant chr16-83747999-T-C is described in ClinVar as [Benign]. Clinvar id is 1241198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5	c.1539-109T>C		intron_variant		ENST00000567109.6
CEDORA	XR_007065143.1	n.142-12081A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6	c.1539-109T>C		intron_variant		1	NM_001257.5	P1
CEDORA	ENST00000570056.2	n.142-19000A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55046 AN: 151692 Hom.: 10030 Cov.: 30

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.368 AC: 368375 AN: 1000922 Hom.: 69181 AF XY: 0.368 AC XY: 188072 AN XY: 511602

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.363 AC: 55086 AN: 151810 Hom.: 10035 Cov.: 30 AF XY: 0.363 AC XY: 26905 AN XY: 74170

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.363

Alfa AF: 0.353 Hom.: 1780

Bravo AF: 0.362

Asia WGS AF: 0.419 AC: 1462 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	-0.85
CADD	Benign	1.2
DANN	Benign	0.53

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: rs16961631; hg19: chr16-83781604; COSMIC: COSV51824858;