16-68813447-C-T

Variant names:

• chr16-68813447-C-T
• rs61756284
• NM_004360.5:c.1272C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001317185.2(CDH1):​c.-344C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,132 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: CDH1 NM_001317185.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -1.37
• Publications: 6 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-68813447-C-T is Benign according to our data. Variant chr16-68813447-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00143 (218/152290) while in subpopulation AMR AF = 0.00418 (64/15298). AF 95% confidence interval is 0.00336. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 218 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317185.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.1272C>T	p.Val424Val	synonymous	Exon 9 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317185.2		c.-344C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 16	NP_001304114.1
	CDH1	NM_001317186.2		c.-548C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 15	NP_001304115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1272C>T	p.Val424Val	synonymous	Exon 9 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.1137+1184C>T		intron	N/A	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.1343C>T		non_coding_transcript_exon	Exon 8 of 15

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000827 AC: 208 AN: 251482 AF XY: 0.000898

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00113 AC: 1659 AN: 1461842 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 821 AN XY: 727222

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86240

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00135 AC: 1504 AN: 1111982

Other (OTH) AF: 0.00106 AC: 64 AN: 60396

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74464

African (AFR) AF: 0.000313 AC: 13 AN: 41550

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00165

EpiCase AF: 0.000818

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	6	not provided (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary diffuse gastric adenocarcinoma (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	CDH1-related disorder (1)
-	-	1	Familial cancer of breast;C1140680:Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.36
DANN	Benign	0.75
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61756284; hg19: chr16-68847350;