rs760899127

Variant names:

• chr16-82858425-C-A
• rs760899127
• NM_001257.5:c.109C>A
• CDH13 p.His37Asn

Your query was ambiguous. Multiple possible variants found:

• chr16-82858425-C-A
• chr16-82858425-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_001257.5(CDH13):c.109C>A (p.His37Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000626 (AC=101) in the gnomAD database across 1,613,582 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000661. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H37R: Uncertain_significance (ClinVar VariationId 4223670, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CDH13 NM_001257.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000661 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH13	NM_001257.5	MANE Select	c.109C>A	p.His37Asn	missense	Exon 2 of 14	NP_001248.1	P55290-1
	CDH13	NM_001220488.2		c.250C>A	p.His84Asn	missense	Exon 3 of 15	NP_001207417.1	P55290-4
	CDH13	NM_001220489.2		c.109C>A	p.His37Asn	missense	Exon 2 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.109C>A	p.His37Asn	missense	Exon 2 of 14	ENSP00000479395.1	P55290-1
	CDH13	ENST00000431540.7	TSL:1	c.109C>A	p.His37Asn	missense	Exon 2 of 5	ENSP00000408632.3	P55290-2
	CDH13	ENST00000567445.1	TSL:1	c.109C>A	p.His37Asn	missense	Exon 2 of 2	ENSP00000456297.1	H3BRL7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000394	AC:6	Hom:0	AN:152180	Cov:33
GnomAD2 exomes	AF: 0.0000281	AC:7	Hom:	AN:249058	Cov:
GnomAD4 exome	AF: 0.0000650	AC:95	Hom:0	AN:1461402	Cov:30
GnomAD4 genome	AF: 0.0000394	AC:6	Hom:0	AN:152180	Cov:33
TOPMed (Bravo)	AF: 0.0000340	AC:9	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000106	AC:5	Hom:0	AN:47208	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000492	6	121906	0.0000315	6	190708

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	20
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.13	N
FuncVEP CTI	Benign	0.028
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Benign	0.90	L
PhyloP100	Benign	1.3
popEVE	Benign	-2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.059
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Varity_R	N/A	0.092
VESM-3B	Benign	-6.8

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760899127;

hg19: chr16-82892030;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar