16-83780039-A-G

Variant names:

• chr16-83780039-A-G
• rs199759196
• NM_001257.5:c.1753A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001257.5(CDH13):​c.1753A>G​(p.Ile585Val) variant causes a missense change. The variant allele was found at a frequency of 0.000556 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: CDH13 NM_001257.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29
• Publications: 5 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]

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035336703).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH13	NM_001257.5	MANE Select	c.1753A>G	p.Ile585Val	missense	Exon 12 of 14	NP_001248.1	P55290-1
	CDH13	NM_001220488.2		c.1894A>G	p.Ile632Val	missense	Exon 13 of 15	NP_001207417.1	P55290-4
	CDH13	NM_001220489.2		c.1636A>G	p.Ile546Val	missense	Exon 11 of 13	NP_001207418.1	P55290-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH13	ENST00000567109.6	TSL:1 MANE Select	c.1753A>G	p.Ile585Val	missense	Exon 12 of 14	ENSP00000479395.1	P55290-1
	CDH13	ENST00000268613.14	TSL:2	c.1894A>G	p.Ile632Val	missense	Exon 13 of 15	ENSP00000268613.10	P55290-4
	CDH13	ENST00000428848.7	TSL:2	c.1636A>G	p.Ile546Val	missense	Exon 11 of 13	ENSP00000394557.3	P55290-5

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000337 AC: 84 AN: 249268 AF XY: 0.000362

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000569 AC: 831 AN: 1461702 Hom.: 1 Cov.: 31 AF XY: 0.000562 AC XY: 409 AN XY: 727136

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000696 AC: 774 AN: 1111866

Other (OTH) AF: 0.000596 AC: 36 AN: 60374

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74448

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000521 Hom.: 1

Bravo AF: 0.000366

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000598 AC: 5

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CDH13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N
PhyloP100		4.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.056
Sift	Benign	0.86	T
Sift4G	Benign	0.53	T
Polyphen		0.0030	B
Vest4		0.17
MVP		0.70
MPC		0.065
ClinPred		0.037	T
GERP RS		4.4
Varity_R		0.053
gMVP		0.29
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs199759196; hg19: chr16-83813644;