rs7188750

Positions:

• chr16-68808992-G-A
• chr16-68808992-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004360.5(CDH1):​c.687+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 762,632 control chromosomes in the GnomAD database, including 13,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4383 hom., cov: 32)
  • Exomes 𝑓: 0.17 (9109 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.619

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=-0.75).
• BP6: Variant 16-68808992-G-A is Benign according to our data. Variant chr16-68808992-G-A is described in ClinVar as [Benign]. Clinvar id is 1259545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.687+144G>A		intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.687+144G>A		intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.-929+144G>A		intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-1133+144G>A		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.687+144G>A		intron_variant		1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33701 AN: 151986 Hom.: 4368 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.166 AC: 101481 AN: 610528 Hom.: 9109 Cov.: 7 AF XY: 0.163 AC XY: 52989 AN XY: 325668

Gnomad4 AFR exome AF: 0.362

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.222 AC: 33763 AN: 152104 Hom.: 4383 Cov.: 32 AF XY: 0.219 AC XY: 16255 AN XY: 74368

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.186

Alfa AF: 0.179 Hom.: 1921

Bravo AF: 0.230

Asia WGS AF: 0.182 AC: 632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.2
DANN	Benign	0.89

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: rs7188750; hg19: chr16-68842895;