rs1555515331

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001797.4(CDH11):​c.999+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDH11
NM_001797.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.2, offset of 10, new splice context is: aggGTaagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-64988156-C-A is Pathogenic according to our data. Variant chr16-64988156-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 523097.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-64988156-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH11NM_001797.4 linkc.999+1G>T splice_donor_variant, intron_variant Intron 7 of 12 ENST00000268603.9 NP_001788.2 P55287-1
CDH11NM_001308392.2 linkc.999+1G>T splice_donor_variant, intron_variant Intron 7 of 13 NP_001295321.1 P55287-2
CDH11NM_001330576.2 linkc.621+1G>T splice_donor_variant, intron_variant Intron 6 of 11 NP_001317505.1 H3BUU9
CDH11XM_047433486.1 linkc.621+1G>T splice_donor_variant, intron_variant Intron 6 of 11 XP_047289442.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH11ENST00000268603.9 linkc.999+1G>T splice_donor_variant, intron_variant Intron 7 of 12 1 NM_001797.4 ENSP00000268603.4 P55287-1
CDH11ENST00000394156.7 linkc.999+1G>T splice_donor_variant, intron_variant Intron 7 of 13 1 ENSP00000377711.3 P55287-2
CDH11ENST00000619158.1 linkc.178G>T p.Val60Leu missense_variant Exon 1 of 1 6 ENSP00000484650.1 A0A087X227
CDH11ENST00000566827.5 linkc.621+1G>T splice_donor_variant, intron_variant Intron 6 of 11 2 ENSP00000457812.1 H3BUU9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453076
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
722444
show subpopulations
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Elsahy-Waters syndrome Pathogenic:1
Apr 27, 2018
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.23
Position offset: -9
DS_DL_spliceai
0.97
Position offset: 1

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.

Other links and lift over

dbSNP: rs1555515331; hg19: chr16-65022059; API