16-68737418-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_004360.5(CDH1):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH1 NM_004360.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004360.5 (CDH1) was described as [Pathogenic] in ClinVar as 239906
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68737418-G-C is Pathogenic according to our data. Variant chr16-68737418-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.3G>C	p.Met1?	start_lost	1/16	ENST00000261769.10
CDH1	NM_001317184.2	c.3G>C	p.Met1?	start_lost	1/15
CDH1	NM_001317185.2	c.-1613G>C		5_prime_UTR_variant	1/16
CDH1	NM_001317186.2	c.-1817G>C		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.3G>C	p.Met1?	start_lost	1/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.3G>C	p.Met1?	start_lost	1/15	1
CDH1	ENST00000566612.5	c.3G>C	p.Met1?	start_lost, NMD_transcript_variant	1/15	1
CDH1	ENST00000566510.5	c.3G>C	p.Met1?	start_lost, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Benign	-0.00073
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.13	B;.;.;.;.
Vest4		0.76
MutPred		1.0		Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);Loss of disorder (P = 0.0796);
MVP		0.79
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68771321;