8-94130944-T-G

Variant names:

• chr8-94130944-T-G
• rs1051624
• NM_004063.4:c.2216A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E739G) has been classified as Uncertain significance.

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.369
• Publications: 42 publications found

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]

ENSG00000304524 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1287378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004063.4. 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
	CDH17	NM_004063.4	MANE Select	c.2216A>C	p.Glu739Ala	missense	Exon 16 of 18	NP_004054.3
	CDH17	NM_001413951.1		c.2273A>C	p.Glu758Ala	missense	Exon 16 of 18	NP_001400880.1
	CDH17	NM_001144663.2		c.2216A>C	p.Glu739Ala	missense	Exon 16 of 18	NP_001138135.1	Q12864

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH17	ENST00000027335.8	TSL:1 MANE Select	c.2216A>C	p.Glu739Ala	missense	Exon 16 of 18	ENSP00000027335.3	Q12864
	CDH17	ENST00000450165.6	TSL:1	c.2216A>C	p.Glu739Ala	missense	Exon 16 of 18	ENSP00000401468.2	Q12864
	CDH17	ENST00000877574.1		c.2273A>C	p.Glu758Ala	missense	Exon 16 of 18	ENSP00000547633.1

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

GnomAD2 exomes AF: 0.512 AC: 128225 AN: 250280 AF XY: 0.518

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 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

African (AFR) AF: 0.295 AC: 9822 AN: 33332

American (AMR) AF: 0.406 AC: 18083 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 14601 AN: 26044

East Asian (EAS) AF: 0.532 AC: 21097 AN: 39652

South Asian (SAS) AF: 0.467 AC: 40104 AN: 85940

European-Finnish (FIN) AF: 0.609 AC: 32435 AN: 53298

Middle Eastern (MID) AF: 0.415 AC: 2386 AN: 5750

European-Non Finnish (NFE) AF: 0.563 AC: 620987 AN: 1103866

Other (OTH) AF: 0.518 AC: 31160 AN: 60106

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

African (AFR) AF: 0.306 AC: 12671 AN: 41368

American (AMR) AF: 0.415 AC: 6329 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1925 AN: 3468

East Asian (EAS) AF: 0.549 AC: 2812 AN: 5120

South Asian (SAS) AF: 0.476 AC: 2287 AN: 4808

European-Finnish (FIN) AF: 0.613 AC: 6433 AN: 10490

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.567 AC: 38540 AN: 67918

Other (OTH) AF: 0.449 AC: 946 AN: 2106

Alfa AF: 0.536 Hom.: 92325

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000048	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.020
Sift	Benign	0.70	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.062
MPC		0.070
ClinPred		0.0048	T
GERP RS		0.45
Varity_R		0.028
gMVP		0.61
Mutation Taster		=98/2	polymorphism (auto)

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

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