16-64948025-G-A

Variant names:

• chr16-64948025-G-A
• rs1333609650
• NM_001797.4:c.1969C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001797.4(CDH11):​c.1969C>T​(p.Arg657Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CDH11 NM_001797.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.42

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH11	NM_001797.4	c.1969C>T	p.Arg657Cys	missense_variant	Exon 13 of 13	ENST00000268603.9	NP_001788.2
CDH11	NM_001330576.2	c.1591C>T	p.Arg531Cys	missense_variant	Exon 12 of 12		NP_001317505.1
CDH11	XM_047433486.1	c.1591C>T	p.Arg531Cys	missense_variant	Exon 12 of 12		XP_047289442.1
CDH11	NM_001308392.2	c.*66C>T		3_prime_UTR_variant	Exon 14 of 14		NP_001295321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH11	ENST00000268603.9	c.1969C>T	p.Arg657Cys	missense_variant	Exon 13 of 13	1	NM_001797.4	ENSP00000268603.4
CDH11	ENST00000394156	c.*66C>T		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000377711.3
CDH11	ENST00000566827.5	c.1591C>T	p.Arg531Cys	missense_variant	Exon 12 of 12	2		ENSP00000457812.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74208

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Teebi hypertelorism syndrome 2 Uncertain:1

Jan 18, 2024

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant CDH11:c.1969C>T, p.(Arg657Cys) which is located in the coding exon 13 of the CDH11 gene, results from a cytosine-to-thymine substitution at nucleotide position c.1969. The arginine at protein position 657 is replaced by cysteine, an amino acid with altered properties. This amino acid position is highly conserved in the available vertebrate species. Furthermore, in silico tools a significance deleterious effect in protein structure and function (REVEL= 0.87). The variant is rare in the overall population (allele frequency=0.00001053 in gnomAD, v4.1.0). In summary, this variant is classified as a variant of unclear significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.77		Gain of sheet (P = 0.0149);.;
MVP		0.94
MPC		0.87
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.73
gMVP		0.94

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

Other links and lift over

dbSNP: rs1333609650; hg19: chr16-64981928; COSMIC: COSV51761650;