NM_001257.5:c.2135-140A>G

Variant names:

• chr16-83794883-A-G
• rs74786055
• NM_001257.5:c.2135-140A>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.2135-140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 659,134 control chromosomes in the GnomAD database, including 2,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (484 hom., cov: 31)
  • Exomes 𝑓: 0.091 (2219 hom.)
• Consequence: CDH13 NM_001257.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.545
• Publications: 0 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=-0.89).
• BP6: Variant 16-83794883-A-G is Benign according to our data. Variant chr16-83794883-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 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.2135-140A>G		intron	N/A	NP_001248.1	P55290-1
	CDH13	NM_001220488.2		c.2276-140A>G		intron	N/A	NP_001207417.1	P55290-4
	CDH13	NM_001220489.2		c.2018-140A>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.2135-140A>G		intron	N/A	ENSP00000479395.1	P55290-1
	CDH13	ENST00000268613.14	TSL:2	c.2276-140A>G		intron	N/A	ENSP00000268613.10	P55290-4
	CDH13	ENST00000428848.7	TSL:2	c.2018-140A>G		intron	N/A	ENSP00000394557.3	P55290-5

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 10606 AN: 139978 Hom.: 483 Cov.: 31

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.0653

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.0624

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0705

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0758

GnomAD4 exome AF: 0.0914 AC: 47418 AN: 519056 Hom.: 2219 AF XY: 0.0924 AC XY: 25703 AN XY: 278120

African (AFR) AF: 0.0497 AC: 678 AN: 13638

American (AMR) AF: 0.132 AC: 3599 AN: 27304

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1194 AN: 16460

East Asian (EAS) AF: 0.213 AC: 5907 AN: 27768

South Asian (SAS) AF: 0.118 AC: 6303 AN: 53496

European-Finnish (FIN) AF: 0.147 AC: 4992 AN: 34010

Middle Eastern (MID) AF: 0.0852 AC: 308 AN: 3616

European-Non Finnish (NFE) AF: 0.0703 AC: 22208 AN: 315786

Other (OTH) AF: 0.0826 AC: 2229 AN: 26978

GnomAD4 genome AF: 0.0757 AC: 10605 AN: 140078 Hom.: 484 Cov.: 31 AF XY: 0.0810 AC XY: 5547 AN XY: 68510

African (AFR) AF: 0.0517 AC: 1592 AN: 30772

American (AMR) AF: 0.0847 AC: 1253 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 216 AN: 3460

East Asian (EAS) AF: 0.156 AC: 800 AN: 5132

South Asian (SAS) AF: 0.115 AC: 546 AN: 4754

European-Finnish (FIN) AF: 0.149 AC: 1549 AN: 10366

Middle Eastern (MID) AF: 0.0690 AC: 20 AN: 290

European-Non Finnish (NFE) AF: 0.0653 AC: 4417 AN: 67616

Other (OTH) AF: 0.0770 AC: 153 AN: 1988

Alfa AF: 0.0614 Hom.: 49

Bravo AF: 0.0657

Asia WGS AF: 0.111 AC: 385 AN: 3460

ClinVar

ClinVar submissions

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	-0.89
CADD	Benign	0.099
DANN	Benign	0.39
PhyloP100		-0.55
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: rs74786055; hg19: chr16-83828488;