NM_001257.5:c.2135-84C>G

Variant names:

• chr16-83794939-C-G
• rs3743617
• NM_001257.5:c.2135-84C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001257.5(CDH13):​c.2135-84C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,243,196 control chromosomes in the GnomAD database, including 37,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4249 hom., cov: 32)
  • Exomes 𝑓: 0.22 (33123 hom.)
• Consequence: CDH13 NM_001257.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630
• Publications: 7 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-83794939-C-G is Benign according to our data. Variant chr16-83794939-C-G is described in ClinVar as Benign. ClinVar VariationId is 1239166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

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.2135-84C>G		intron	N/A	NP_001248.1	P55290-1
	CDH13	NM_001220488.2		c.2276-84C>G		intron	N/A	NP_001207417.1	P55290-4
	CDH13	NM_001220489.2		c.2018-84C>G		intron	N/A	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.2135-84C>G		intron	N/A	ENSP00000479395.1	P55290-1
	CDH13	ENST00000268613.14	TSL:2	c.2276-84C>G		intron	N/A	ENSP00000268613.10	P55290-4
	CDH13	ENST00000428848.7	TSL:2	c.2018-84C>G		intron	N/A	ENSP00000394557.3	P55290-5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31321 AN: 151870 Hom.: 4250 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.221 AC: 241567 AN: 1091208 Hom.: 33123 AF XY: 0.224 AC XY: 123925 AN XY: 552882

African (AFR) AF: 0.0945 AC: 2432 AN: 25734

American (AMR) AF: 0.444 AC: 15757 AN: 35522

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 5509 AN: 23232

East Asian (EAS) AF: 0.660 AC: 22923 AN: 34748

South Asian (SAS) AF: 0.318 AC: 23221 AN: 73010

European-Finnish (FIN) AF: 0.238 AC: 11470 AN: 48272

Middle Eastern (MID) AF: 0.302 AC: 1545 AN: 5108

European-Non Finnish (NFE) AF: 0.185 AC: 147523 AN: 797622

Other (OTH) AF: 0.233 AC: 11187 AN: 47960

GnomAD4 genome AF: 0.206 AC: 31326 AN: 151988 Hom.: 4249 Cov.: 32 AF XY: 0.217 AC XY: 16095 AN XY: 74262

African (AFR) AF: 0.0948 AC: 3933 AN: 41476

American (AMR) AF: 0.363 AC: 5535 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3165 AN: 5138

South Asian (SAS) AF: 0.342 AC: 1645 AN: 4816

European-Finnish (FIN) AF: 0.246 AC: 2592 AN: 10542

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.190 AC: 12936 AN: 67968

Other (OTH) AF: 0.234 AC: 493 AN: 2106

Alfa AF: 0.184 Hom.: 395

Bravo AF: 0.211

Asia WGS AF: 0.444 AC: 1544 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.34
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism (auto)

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: rs3743617; hg19: chr16-83828544;