16-68737387-C-G

Position:

• chr16-68737387-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004360.5(CDH1):​c.-29C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,376,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.91

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-68737387-C-G is Benign according to our data. Variant chr16-68737387-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384067.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.-29C>G		5_prime_UTR_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-29C>G		5_prime_UTR_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1644C>G		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1848C>G		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.-29C>G		5_prime_UTR_variant	1/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.-29C>G		5_prime_UTR_variant	1/15	1		ENSP00000414946
CDH1	ENST00000566612.5	c.-29C>G		5_prime_UTR_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000566510.5	c.-29C>G		5_prime_UTR_variant, NMD_transcript_variant	1/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 2 AN: 125392 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000434

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 14 AN: 1376680 Hom.: 0 Cov.: 29 AF XY: 0.0000118 AC XY: 8 AN XY: 679184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Aug 01, 2022

BS2_Supporting (PMID: 30311375) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.8
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: rs1057521843; hg19: chr16-68771290;