rs1555509640

Positions:

• chr16-68737436-C-A
• chr16-68737436-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004360.5(CDH1):​c.21C>A​(p.Ser7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. S7T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09291226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.21C>A	p.Ser7Arg	missense_variant	1/16	ENST00000261769.10
CDH1	NM_001317184.2	c.21C>A	p.Ser7Arg	missense_variant	1/15
CDH1	NM_001317185.2	c.-1595C>A		5_prime_UTR_variant	1/16
CDH1	NM_001317186.2	c.-1799C>A		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.21C>A	p.Ser7Arg	missense_variant	1/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.21C>A	p.Ser7Arg	missense_variant	1/15	1
CDH1	ENST00000566612.5	c.21C>A	p.Ser7Arg	missense_variant, NMD_transcript_variant	1/15	1
CDH1	ENST00000566510.5	c.21C>A	p.Ser7Arg	missense_variant, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382824 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 682776

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

Dec 05, 2023

This missense variant replaces serine with arginine at codon 7 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.093	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.62	N;.;.;.;N
REVEL	Benign	0.046
Sift	Benign	0.36	T;.;.;.;T
Sift4G	Benign	0.43	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.13
MutPred		0.48		Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);
MVP		0.61
MPC		0.35
ClinPred		0.20	T
GERP RS		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.059
gMVP		0.43

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: chr16-68771339;