8-94130944-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004063.4(CDH17):c.2216A>C(p.Glu739Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,604,310 control chromosomes in the GnomAD database, including 237,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18585 hom., cov: 31)
  • Exomes 𝑓: 0.54 (219104 hom.)
• Consequence: CDH17 NM_004063.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.369

Genes affected

CDH17 (HGNC:1756): (cadherin 17) This gene is a member of the cadherin superfamily, genes encoding calcium-dependent, membrane-associated glycoproteins. The encoded protein is cadherin-like, consisting of an extracellular region, containing 7 cadherin domains, and a transmembrane region but lacking the conserved cytoplasmic domain. The protein is a component of the gastrointestinal tract and pancreatic ducts, acting as an intestinal proton-dependent peptide transporter in the first step in oral absorption of many medically important peptide-based drugs. The protein may also play a role in the morphological organization of liver and intestine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.781197E-5).
• BP6: Variant 8-94130944-T-G is Benign according to our data. Variant chr8-94130944-T-G is described in ClinVar as [Benign]. Clinvar id is 1287378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH17	NM_004063.4	c.2216A>C	p.Glu739Ala	missense_variant	16/18	ENST00000027335.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH17	ENST00000027335.8	c.2216A>C	p.Glu739Ala	missense_variant	16/18	1	NM_004063.4	P1
CDH17	ENST00000450165.6	c.2216A>C	p.Glu739Ala	missense_variant	16/18	1		P1
CDH17	ENST00000441892.6	c.1574A>C	p.Glu525Ala	missense_variant	12/13	2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72572 AN: 151626 Hom.: 18594 Cov.: 31

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.447

GnomAD3 exomes AF: 0.512 AC: 128225 AN: 250280 Hom.: 34014 AF XY: 0.518 AC XY: 70047 AN XY: 135206

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.549

Gnomad SAS exome AF: 0.465

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.544 AC: 790675 AN: 1452568 Hom.: 219104 Cov.: 33 AF XY: 0.543 AC XY: 392771 AN XY: 723090

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.518

GnomAD4 genome AF: 0.478 AC: 72582 AN: 151742 Hom.: 18585 Cov.: 31 AF XY: 0.477 AC XY: 35318 AN XY: 74092

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.555

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.449

Alfa AF: 0.542 Hom.: 48131

Bravo AF: 0.455

TwinsUK AF: 0.561 AC: 2081

ALSPAC AF: 0.551 AC: 2124

ESP6500AA AF: 0.308 AC: 1359

ESP6500EA AF: 0.558 AC: 4801

ExAC AF: 0.512 AC: 62133

Asia WGS AF: 0.495 AC: 1720 AN: 3478

EpiCase AF: 0.554

EpiControl AF: 0.550

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2020

This variant is associated with the following publications: (PMID: 23326130) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.5
Dann	Benign	0.14
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
MetaRNN	Benign	0.000048	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.062
MPC		0.070
ClinPred		0.0048	T
GERP RS		0.45
Varity_R		0.028
gMVP		0.61

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: rs1051624; hg19: chr8-95143172; COSMIC: COSV50337541;