8-94148783-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004063.4(CDH17):c.1888G>A(p.Gly630Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,594,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: CDH17 NM_004063.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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]

LOC105375647 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05231455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH17	NM_004063.4	c.1888G>A	p.Gly630Arg	missense_variant	14/18	ENST00000027335.8
LOC105375647	XR_007061012.1	n.518+4510C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH17	ENST00000027335.8	c.1888G>A	p.Gly630Arg	missense_variant	14/18	1	NM_004063.4	P1
CDH17	ENST00000450165.6	c.1888G>A	p.Gly630Arg	missense_variant	14/18	1		P1
CDH17	ENST00000441892.6	c.1246G>A	p.Gly416Arg	missense_variant	10/13	2
CDH17	ENST00000520952.1	c.*56G>A		3_prime_UTR_variant, NMD_transcript_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.0000610 AC: 9 AN: 147482 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000428

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 31 AN: 240344 Hom.: 0 AF XY: 0.000138 AC XY: 18 AN XY: 130082

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.000276

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000581 AC: 84 AN: 1446438 Hom.: 0 Cov.: 33 AF XY: 0.0000667 AC XY: 48 AN XY: 719414

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000437

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000261

Gnomad4 FIN exome AF: 0.0000570

Gnomad4 NFE exome AF: 0.0000263

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000610 AC: 9 AN: 147580 Hom.: 0 Cov.: 29 AF XY: 0.0000699 AC XY: 5 AN XY: 71542

Gnomad4 AFR AF: 0.000100

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.000429

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000357 Hom.: 0

ExAC AF: 0.0000741 AC: 9

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 30, 2023

The c.1888G>A (p.G630R) alteration is located in exon 14 (coding exon 13) of the CDH17 gene. This alteration results from a G to A substitution at nucleotide position 1888, causing the glycine (G) at amino acid position 630 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.79	P;P;P
Vest4		0.28
MutPred		0.48		Loss of catalytic residue at A629 (P = 0.0384);.;Loss of catalytic residue at A629 (P = 0.0384);
MVP		0.69
MPC		0.10
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.45

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: rs201852873; hg19: chr8-95161011; COSMIC: COSV50325928;