16-64950887-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001797.4(CDH11):c.1774G>A(p.Val592Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH11 NM_001797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40096664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH11	NM_001797.4	c.1774G>A	p.Val592Ile	missense_variant	12/13	ENST00000268603.9
CDH11	NM_001308392.2	c.1774G>A	p.Val592Ile	missense_variant	12/14
CDH11	NM_001330576.2	c.1396G>A	p.Val466Ile	missense_variant	11/12
CDH11	XM_047433486.1	c.1396G>A	p.Val466Ile	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH11	ENST00000268603.9	c.1774G>A	p.Val592Ile	missense_variant	12/13	1	NM_001797.4	P1
CDH11	ENST00000394156.7	c.1774G>A	p.Val592Ile	missense_variant	12/14	1
CDH11	ENST00000566827.5	c.1396G>A	p.Val466Ile	missense_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.1774G>A (p.V592I) alteration is located in exon 12 (coding exon 10) of the CDH11 gene. This alteration results from a G to A substitution at nucleotide position 1774, causing the valine (V) at amino acid position 592 to be replaced by an isoleucine (I). 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	0.12
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.084
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.78	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.072	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.096	B;B;.
Vest4		0.29
MutPred		0.61		Loss of ubiquitination at K591 (P = 0.1216);Loss of ubiquitination at K591 (P = 0.1216);.;
MVP		0.73
MPC		0.15
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.13
gMVP		0.59

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: chr16-64984790;