rs1181682630

Positions:

• chr16-68819356-C-A
• chr16-68819356-C-G
• chr16-68819356-C-T

Variant summary

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

The NM_004360.5(CDH1):​c.1642C>A​(p.Leu548Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 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: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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]

(HGNC:):

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.1642C>A	p.Leu548Met	missense_variant	11/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1459C>A	p.Leu487Met	missense_variant	10/15		NP_001304113.1
CDH1	NM_001317185.2	c.94C>A	p.Leu32Met	missense_variant	11/16		NP_001304114.1
CDH1	NM_001317186.2	c.-254-2645C>A		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1642C>A	p.Leu548Met	missense_variant	11/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.264-3697G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N;.;.;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.18	T;.;.;.;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.96	D;.;.;.;.
Vest4		0.29
MutPred		0.81		Gain of disorder (P = 0.0996);Gain of disorder (P = 0.0996);.;Gain of disorder (P = 0.0996);.;
MVP		0.72
MPC		0.43
ClinPred		0.49	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.37

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: chr16-68853259;