chr16-89282336-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B.

Score: 18 - Oncogenic
18
-12 -7 -6 -1 0 5 6 9 10 12
PVS1PM2PP5_Very_Strong

The NM_013275.6(ANKRD11):​c.4206C>G​(p.Tyr1402*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y1402Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

ANKRD11
NM_013275.6 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.357

Publications

0 publications found
Variant links:
Genes affected
ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]
ANKRD11 Gene-Disease associations (from GenCC):
  • KBG syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, Illumina, ClinGen
  • congenital heart defects, multiple types
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-89282336-G-C is Pathogenic according to our data. Variant chr16-89282336-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 579848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD11NM_013275.6 linkc.4206C>G p.Tyr1402* stop_gained Exon 9 of 13 ENST00000301030.10 NP_037407.4 Q6UB99
ANKRD11NM_001256182.2 linkc.4206C>G p.Tyr1402* stop_gained Exon 10 of 14 NP_001243111.1 Q6UB99
ANKRD11NM_001256183.2 linkc.4206C>G p.Tyr1402* stop_gained Exon 9 of 13 NP_001243112.1 Q6UB99

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD11ENST00000301030.10 linkc.4206C>G p.Tyr1402* stop_gained Exon 9 of 13 5 NM_013275.6 ENSP00000301030.4 Q6UB99

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

KBG syndrome Pathogenic:3
Feb 18, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 30, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25413698). This variant has been reported in an individual affected with KBG syndrome (PMID: 27667800). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr1402*) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. -

May 30, 2022
Institute of Human Genetics Munich, TUM University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
May 08, 2022
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27667800) -

Intellectual disability Pathogenic:1
Dec 01, 2017
Diagnostic Laboratory, Strasbourg University Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.24
N
PhyloP100
-0.36
Vest4
0.69
GERP RS
-2.5
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs749632782; hg19: chr16-89348744; API