16-64948049-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001797.4(CDH11):c.1945A>G(p.Ile649Val) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,613,982 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 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CDH11
NM_001797.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

CDH11 (HGNC:1750): (cadherin 11) This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance. [provided by RefSeq, Jul 2008]

CDH11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1671871).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000237 (36/152108) while in subpopulation AMR AF= 0.000589 (9/15280). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH11	NM_001797.4 link	c.1945A>G	p.Ile649Val	missense_variant	Exon 13 of 13	ENST00000268603.9	NP_001788.2	P55287-1
CDH11	NM_001330576.2 link	c.1567A>G	p.Ile523Val	missense_variant	Exon 12 of 12		NP_001317505.1	H3BUU9
CDH11	XM_047433486.1 link	c.1567A>G	p.Ile523Val	missense_variant	Exon 12 of 12		XP_047289442.1
CDH11	NM_001308392.2 link	c.*42A>G		3_prime_UTR_variant	Exon 14 of 14		NP_001295321.1	P55287-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH11	ENST00000268603.9 link	c.1945A>G	p.Ile649Val	missense_variant	Exon 13 of 13	1	NM_001797.4	ENSP00000268603.4	P55287-1
CDH11	ENST00000394156 link	c.*42A>G		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000377711.3	P55287-2
CDH11	ENST00000566827.5 link	c.1567A>G	p.Ile523Val	missense_variant	Exon 12 of 12	2		ENSP00000457812.1	H3BUU9

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251400

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000323

AC:

472

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

229

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000378

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000237

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000384

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1945A>G (p.I649V) alteration is located in exon 13 (coding exon 11) of the CDH11 gene. This alteration results from a A to G substitution at nucleotide position 1945, causing the isoleucine (I) at amino acid position 649 to be replaced by a valine (V). 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

0.31

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

-0.025

MutationAssessor

Benign

1.7

L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.061

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.89

P;.

Vest4

0.37

MVP

0.61

MPC

0.67

ClinPred

0.11

GERP RS

5.6

Varity_R

0.18

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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