Genetic Variant CDH6:p.Thr67Ala (chr5-31267672-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004932.4(CDH6):c.199A>G(p.Thr67Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CDH6
NM_004932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94

Variant links:

Genes affected

CDH6 (HGNC:1765): (cadherin 6) This gene encodes a member of the cadherin superfamily. Cadherins are membrane glycoproteins that mediate homophilic cell-cell adhesion and play critical roles in cell differentiation and morphogenesis. The encoded protein is a type II cadherin and may play a role in kidney development as well as endometrium and placenta formation. Decreased expression of this gene may be associated with tumor growth and metastasis. [provided by RefSeq, May 2011]

CDH6 links:

ENSG00000254138 (HGNC:):

ENSG00000254138 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.240446).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH6	NM_004932.4 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 2 of 12	ENST00000265071.3	NP_004923.1	P55285-1
CDH6	NM_001362435.2 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 2 of 11		NP_001349364.1
CDH6	XM_011513921.4 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 2 of 12		XP_011512223.1	P55285-1
CDH6	XM_047416591.1 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 2 of 12		XP_047272547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH6	ENST00000265071.3 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 2 of 12	2	NM_004932.4	ENSP00000265071.2	P55285-1
CDH6	ENST00000514738.5 link	c.34A>G	p.Thr12Ala	missense_variant	Exon 2 of 11	1		ENSP00000424843.1	D6RF86
ENSG00000254138	ENST00000523584.1 link	n.-62T>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249168

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000440

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199A>G (p.T67A) alteration is located in exon 2 (coding exon 1) of the CDH6 gene. This alteration results from a A to G substitution at nucleotide position 199, causing the threonine (T) at amino acid position 67 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

T;D

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.094

MutationAssessor

Benign

1.5

.;L

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.19

Sift

Benign

0.18

T;T

Sift4G

Benign

0.078

T;T

Polyphen

0.030

.;B

Vest4

0.15

MutPred

0.50

.;Loss of phosphorylation at T67 (P = 0.0726);

MVP

0.53

MPC

1.4

ClinPred

0.17

GERP RS

5.8

Varity_R

0.32

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over