chr20-59984752-C-T

Position:

• chr20-59984752-C-T

Variant summary

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

The NM_177980.4(CDH26):​c.655C>T​(p.Arg219Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: CDH26 NM_177980.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.789

Genes affected

CDH26 (HGNC:15902): (cadherin 26) This gene encodes a member of the cadherin protein family. Cadherins are a family of calcium-dependent adhesion molecules that mediate cell-cell adhesion in all solid tissues and modulate a wide variety of processes, including cell polarization, migration and differentiation. Cadherin domains occur as repeats in the extracellular region and are thought to contribute to the sorting of heterogeneous cell types and the maintenance of orderly structures such as epithelium. This protein is expressed in gastrointestinal epithelial cells and may be upregulated during allergic inflammation. This protein interacts with alpha integrins and may also be involved in leukocyte migration and adhesion. [provided by RefSeq, Jan 2017]

CDH26 (HGNC:):

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=0.1153478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH26	NM_177980.4	c.655C>T	p.Arg219Trp	missense_variant	6/18	ENST00000348616.9	NP_817089.1
CDH26	NR_145482.2	n.977C>T		non_coding_transcript_exon_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH26	ENST00000348616.9	c.655C>T	p.Arg219Trp	missense_variant	6/18	2	NM_177980.4	ENSP00000339390.4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251102 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135722

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000361 AC: 527 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.000342 AC XY: 249 AN XY: 727074

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000446

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74328

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.655C>T (p.R219W) alteration is located in exon 6 (coding exon 6) of the CDH26 gene. This alteration results from a C to T substitution at nucleotide position 655, causing the arginine (R) at amino acid position 219 to be replaced by a tryptophan (W). 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	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.51
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Vest4		0.29
MVP		0.40
MPC		0.14
ClinPred		0.035	T
GERP RS		-6.3
Varity_R		0.050
gMVP		0.31

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: rs144821881; hg19: chr20-58559807;