rs199545571

Positions:

• chr16-68808881-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):​c.687+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,610,842 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0520

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-68808881-G-A is Benign according to our data. Variant chr16-68808881-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 560833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000329 (50/152196) while in subpopulation EAS AF= 0.00386 (20/5180). AF 95% confidence interval is 0.00256. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.687+33G>A		intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.687+33G>A		intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.-929+33G>A		intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-1133+33G>A		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.687+33G>A		intron_variant		1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000447 AC: 111 AN: 248062 Hom.: 2 AF XY: 0.000492 AC XY: 66 AN XY: 134274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00330

Gnomad EAS exome AF: 0.00164

Gnomad SAS exome AF: 0.000689

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000329 AC: 480 AN: 1458646 Hom.: 3 Cov.: 31 AF XY: 0.000351 AC XY: 255 AN XY: 725686

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00353

Gnomad4 SAS exome AF: 0.000685

Gnomad4 FIN exome AF: 0.000307

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74412

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000897 Hom.: 0

Bravo AF: 0.000242

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.7
DANN	Benign	0.75

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: rs199545571; hg19: chr16-68842784; COSMIC: COSV55730410; COSMIC: COSV55730410;