16-68801804-G-C

Variant names:

• chr16-68801804-G-C
• NM_004360.5:c.298G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_004360.5(CDH1):​c.298G>C​(p.Val100Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28824586).
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.298G>C	p.Val100Leu	missense_variant	Exon 3 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.298G>C	p.Val100Leu	missense_variant	Exon 3 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1318G>C		5_prime_UTR_variant	Exon 3 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1522G>C		5_prime_UTR_variant	Exon 3 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.298G>C	p.Val100Leu	missense_variant	Exon 3 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.56
DEOGEN2	Benign	0.24	T;T;T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.84	T;T;T;T;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;.;.;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Benign	0.082
Sift	Benign	0.039	D;.;.;.;D
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.82	P;.;.;.;.
Vest4		0.25
MutPred		0.69		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.71
MPC		0.30
ClinPred		0.099	T
GERP RS		-0.70
Varity_R		0.11
gMVP		0.36

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: chr16-68835707;