16-83032103-T-C

Variant names:

• chr16-83032103-T-C
• NM_001257.5:c.251T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001257.5(CDH13):​c.251T>C​(p.Leu84Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH13 NM_001257.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

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.251T>C	p.Leu84Pro	missense	Exon 3 of 14	NP_001248.1	P55290-1
	CDH13	NM_001220488.2		c.392T>C	p.Leu131Pro	missense	Exon 4 of 15	NP_001207417.1	P55290-4
	CDH13	NM_001220489.2		c.251T>C	p.Leu84Pro	missense	Exon 3 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.251T>C	p.Leu84Pro	missense	Exon 3 of 14	ENSP00000479395.1	P55290-1
	CDH13	ENST00000431540.7	TSL:1	c.251T>C	p.Leu84Pro	missense	Exon 3 of 5	ENSP00000408632.3	P55290-2
	CDH13	ENST00000268613.14	TSL:2	c.392T>C	p.Leu131Pro	missense	Exon 4 of 15	ENSP00000268613.10	P55290-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461056 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.79
MutPred		0.78		Loss of stability (P = 0.0017)
MVP		0.83
MPC		0.48
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.84

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

hg19: chr16-83065708;