16-64948049-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

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 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/exons	MANE	UniProt
CDH11	NM_001797.4	c.1945A>G	p.Ile649Val	missense_variant	13/13	ENST00000268603.9
CDH11	NM_001330576.2	c.1567A>G	p.Ile523Val	missense_variant	12/12
CDH11	XM_047433486.1	c.1567A>G	p.Ile523Val	missense_variant	12/12
CDH11	NM_001308392.2	c.*42A>G		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH11	ENST00000268603.9	c.1945A>G	p.Ile649Val	missense_variant	13/13	1	NM_001797.4	P1
CDH11	ENST00000394156.7	c.*42A>G		3_prime_UTR_variant	14/14	1
CDH11	ENST00000566827.5	c.1567A>G	p.Ile523Val	missense_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152108 Hom.: 0 Cov.: 32

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: 70 AN: 251400 Hom.: 0 AF XY: 0.000316 AC XY: 43 AN XY: 135880

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.: 0 Cov.: 33 AF XY: 0.000315 AC XY: 229 AN XY: 727234

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: 36 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74308

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.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000218

EpiControl AF: 0.000711

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

Aug 23, 2021

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	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
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	T
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

Other links and lift over

dbSNP: rs201059793; hg19: chr16-64981952;