chr16-89284129-CTTTTT-C

Variant names:

• chr16-89284129-CTTTTT-C
• rs886039902
• NM_013275.6:c.2408_2412delAAAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_013275.6(ANKRD11):​c.2408_2412delAAAAA​(p.Lys803ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,456,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 4.98
• Publications: 5 publications found

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

ACMG classification

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 16-89284129-CTTTTT-C is Pathogenic according to our data. Variant chr16-89284129-CTTTTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 266033.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
ANKRD11	NM_013275.6	c.2408_2412delAAAAA	p.Lys803ArgfsTer5	frameshift_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.2408_2412delAAAAA	p.Lys803ArgfsTer5	frameshift_variant	Exon 10 of 14		NP_001243111.1
ANKRD11	NM_001256183.2	c.2408_2412delAAAAA	p.Lys803ArgfsTer5	frameshift_variant	Exon 9 of 13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.2408_2412delAAAAA	p.Lys803ArgfsTer5	frameshift_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456390 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 723966

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.00 AC: 0 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 84166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110440

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:9

Apr 15, 2016

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 01, 2021

Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys803Argfs*5) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). ClinVar contains an entry for this variant (Variation ID: 266033). For these reasons, this variant has been classified as Pathogenic. -

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially reported on 2018-01-09 by GTR ID of laboratory name 506154. The reporting laboratory might also submit to ClinVar. -

May 28, 2020

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Mar 18, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27667800, 25533962, 28191890, 29224748, 28135719, 32124548) -

Dec 12, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANKRD11: PVS1, PM2 -

Global developmental delay Pathogenic:1

Jan 22, 2021

Institute for Human Genetics, University Hospital Essen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Sep 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2408_2412delAAAAA (p.K803Rfs*5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 to 2412, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated individuals with clinical features of KBG syndrome (Parenti, 2021; Gnazzo, 2020). Additional heterozygous individuals with ANKRD11 variants have been reported in the literature (Low, 2016; Bestetti, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

ANKRD11-related disorder Pathogenic:1

Mar 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ANKRD11 c.2408_2412del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys803Argfs*5). This variant has been reported in multiple unrelated individuals with KBG syndrome (Low et al. 2016. PubMed ID: 27667800; Bianchi et al. 2017. PubMed ID: 29224748; Wright et al. 2021. PubMed ID: 33149276; Parenti et al. 2021. PubMed ID: 33955014; Marangoni et al. 2021. PubMed ID: 34906519; Digilio et al. 2021. PubMed ID: 34971082; Tal-Ben Ishay et al. 2021. PubMed ID: 35052376; Loberti et al. 2022. PubMed ID: 35861666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886039902; hg19: chr16-89350537;