16-68737420-G-A

Position:

• chr16-68737420-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000261769.10(CDH1):​c.5G>A​(p.Gly2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 ENST00000261769.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.5G>A	p.Gly2Asp	missense_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.5G>A	p.Gly2Asp	missense_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1611G>A		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1815G>A		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.5G>A	p.Gly2Asp	missense_variant	1/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.5G>A	p.Gly2Asp	missense_variant	1/15	1		ENSP00000414946
CDH1	ENST00000566612.5	c.5G>A	p.Gly2Asp	missense_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000566510.5	c.5G>A	p.Gly2Asp	missense_variant, NMD_transcript_variant	1/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1381472 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681970

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.58	T;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;.;.;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.012	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.79	P;.;.;.;.
Vest4		0.57
MutPred		0.40		Loss of catalytic residue at G2 (P = 0.0258);Loss of catalytic residue at G2 (P = 0.0258);Loss of catalytic residue at G2 (P = 0.0258);Loss of catalytic residue at G2 (P = 0.0258);Loss of catalytic residue at G2 (P = 0.0258);
MVP		0.84
MPC		1.0
ClinPred		0.92	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.68

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: rs878854692; hg19: chr16-68771323;