rs1048612

chr16-83783414-A-Gchr16-83783414-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001257.5(CDH13):c.2076A>G(p.Ala692=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,613,744 control chromosomes in the GnomAD database, including 526,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50344 hom., cov: 32)
  • Exomes 𝑓: 0.81 (475825 hom.)
• Consequence: CDH13 NM_001257.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.86

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]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-83783414-A-G is Benign according to our data. Variant chr16-83783414-A-G is described in ClinVar as [Benign]. Clinvar id is 257647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5	c.2076A>G	p.Ala692=	synonymous_variant	13/14	ENST00000567109.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6	c.2076A>G	p.Ala692=	synonymous_variant	13/14	1	NM_001257.5	P1

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123619 AN: 152044 Hom.: 50309 Cov.: 32

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.823

GnomAD3 exomes AF: 0.811 AC: 202165 AN: 249184 Hom.: 82067 AF XY: 0.810 AC XY: 109461 AN XY: 135188

Gnomad AFR exome AF: 0.835

Gnomad AMR exome AF: 0.851

Gnomad ASJ exome AF: 0.785

Gnomad EAS exome AF: 0.797

Gnomad SAS exome AF: 0.809

Gnomad FIN exome AF: 0.804

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.807 AC: 1178904 AN: 1461582 Hom.: 475825 Cov.: 58 AF XY: 0.806 AC XY: 586364 AN XY: 727084

Gnomad4 AFR exome AF: 0.835

Gnomad4 AMR exome AF: 0.851

Gnomad4 ASJ exome AF: 0.784

Gnomad4 EAS exome AF: 0.801

Gnomad4 SAS exome AF: 0.812

Gnomad4 FIN exome AF: 0.806

Gnomad4 NFE exome AF: 0.805

Gnomad4 OTH exome AF: 0.801

GnomAD4 genome AF: 0.813 AC: 123707 AN: 152162 Hom.: 50344 Cov.: 32 AF XY: 0.813 AC XY: 60455 AN XY: 74384

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.841

Gnomad4 ASJ AF: 0.780

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.801

Gnomad4 OTH AF: 0.816

Alfa AF: 0.807 Hom.: 71409

Bravo AF: 0.819

Asia WGS AF: 0.803 AC: 2793 AN: 3478

EpiCase AF: 0.808

EpiControl AF: 0.806

ClinVar

Significance: 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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.045
Dann	Benign	0.29

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: rs1048612; hg19: chr16-83817019; COSMIC: COSV51841205;