16-64947921-G-C

Position:

• chr16-64947921-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001797.4(CDH11):​c.2073C>G​(p.Ile691Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CDH11 NM_001797.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.340

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060406327).
• BP6: Variant 16-64947921-G-C is Benign according to our data. Variant chr16-64947921-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3025636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00238 (363/152228) while in subpopulation AFR AF= 0.00801 (333/41550). AF 95% confidence interval is 0.00731. There are 1 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH11	NM_001797.4	c.2073C>G	p.Ile691Met	missense_variant	13/13	ENST00000268603.9
CDH11	NM_001330576.2	c.1695C>G	p.Ile565Met	missense_variant	12/12
CDH11	XM_047433486.1	c.1695C>G	p.Ile565Met	missense_variant	12/12
CDH11	NM_001308392.2	c.*170C>G		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH11	ENST00000268603.9	c.2073C>G	p.Ile691Met	missense_variant	13/13	1	NM_001797.4	P1
CDH11	ENST00000394156.7	c.*170C>G		3_prime_UTR_variant	14/14	1
CDH11	ENST00000566827.5	c.1695C>G	p.Ile565Met	missense_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00801

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000529 AC: 133 AN: 251488 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135918

Gnomad AFR exome AF: 0.00707

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.000171 AC XY: 124 AN XY: 727246

Gnomad4 AFR exome AF: 0.00699

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152228 Hom.: 1 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74416

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.00277

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDH11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

CDH11: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.5
DANN	Benign	0.93
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.22
Sift	Benign	0.086	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0030	B;.
Vest4		0.17
MVP		0.58
MPC		0.19
ClinPred		0.0042	T
GERP RS		2.1
Varity_R		0.064
gMVP		0.58

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: rs35145978; hg19: chr16-64981824;