16-68823948-A-T

Position:

• chr16-68823948-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004360.5(CDH1):​c.2164+322A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 149,712 control chromosomes in the GnomAD database, including 1,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.070 (1071 hom., cov: 31)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.174

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 16-68823948-A-T is Benign according to our data. Variant chr16-68823948-A-T is described in ClinVar as [Benign]. Clinvar id is 1222241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2164+322A>T		intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1981+322A>T		intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.616+322A>T		intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.199+322A>T		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2164+322A>T		intron_variant		1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10549 AN: 149658 Hom.: 1072 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0131

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.0426

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0704 AC: 10546 AN: 149712 Hom.: 1071 Cov.: 31 AF XY: 0.0693 AC XY: 5052 AN XY: 72928

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00130

Gnomad4 OTH AF: 0.0420

Alfa AF: 0.0417 Hom.: 74

Bravo AF: 0.0826

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.9
DANN	Benign	0.78

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: rs10500545; hg19: chr16-68857851;