16-66909363-C-T

Variant names:

• chr16-66909363-C-T
• rs140072479
• NM_004062.4:c.2296G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004062.4(CDH16):​c.2296G>A​(p.Val766Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,397,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CDH16 NM_004062.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.391

Genes affected

CDH16 (HGNC:1755): (cadherin 16) This gene is a member of the cadherin superfamily, genes encoding calcium-dependent, membrane-associated glycoproteins. Mapped to a previously identified cluster of cadherin genes on chromosome 16q22.1, the gene localizes with superfamily members CDH1, CDH3, CDH5, CDH8 and CDH11. The protein consists of an extracellular domain containing 6 cadherin domains, a transmembrane region and a truncated cytoplasmic domain but lacks the prosequence and tripeptide HAV adhesion recognition sequence typical of most classical cadherins. Expression is exclusively in kidney, where the protein functions as the principal mediator of homotypic cellular recognition, playing a role in the morphogenic direction of tissue development. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112303734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH16	NM_004062.4	c.2296G>A	p.Val766Met	missense_variant	Exon 17 of 18	ENST00000299752.9	NP_004053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH16	ENST00000299752.9	c.2296G>A	p.Val766Met	missense_variant	Exon 17 of 18	1	NM_004062.4	ENSP00000299752.4

Frequencies

GnomAD3 genomes AF: 0.0000346 AC: 5 AN: 144652 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000233

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249484 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000239 AC: 30 AN: 1252710 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 18 AN XY: 621766

Gnomad4 AFR exome AF: 0.0000366

Gnomad4 AMR exome AF: 0.0000521

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000255

Gnomad4 OTH exome AF: 0.0000215

GnomAD4 genome AF: 0.0000346 AC: 5 AN: 144652 Hom.: 0 Cov.: 32 AF XY: 0.0000284 AC XY: 2 AN XY: 70434

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.000137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000233

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2296G>A (p.V766M) alteration is located in exon 17 (coding exon 16) of the CDH16 gene. This alteration results from a G to A substitution at nucleotide position 2296, causing the valine (V) at amino acid position 766 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	.;T;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.073	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.0080	B;B;.;.;.
Vest4		0.32
MVP		0.44
MPC		0.069
ClinPred		0.11	T
GERP RS		0.81
Varity_R		0.040
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs140072479; hg19: chr16-66943266;