chr16-89279749-C-CG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_013275.6(ANKRD11):c.6792dupC(p.Ala2265ArgfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2264P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ANKRD11
NM_013275.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: -3.15

Publications

2 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

ANKRD11 links:

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 16-89279749-C-CG is Pathogenic according to our data. Variant chr16-89279749-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 521294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD11	NM_013275.6	MANE Select	c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 9 of 13	NP_037407.4
ANKRD11	NM_001256182.2		c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 10 of 14	NP_001243111.1
ANKRD11	NM_001256183.2		c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 9 of 13	NP_001243112.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 9 of 13	ENSP00000301030.4
ANKRD11	ENST00000378330.7	TSL:1	c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 10 of 14	ENSP00000367581.2
ANKRD11	ENST00000642600.2		c.6792dupC	p.Ala2265ArgfsTer8	frameshift	Exon 9 of 13	ENSP00000495226.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000242

AC:

AN:

123718

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000305

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.29e-7

AC:

AN:

1371808

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

675444

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31382

American (AMR)

AF:

0.00

AC:

AN:

35148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23952

East Asian (EAS)

AF:

0.00

AC:

AN:

35790

South Asian (SAS)

AF:

0.00

AC:

AN:

78500

European-Finnish (FIN)

AF:

0.0000294

AC:

AN:

34004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4792

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071126

Other (OTH)

AF:

0.00

AC:

AN:

57114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KBG syndrome

Pathogenic:5

Jun 13, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a single nucleotide duplication (dupC) in exon 9 of 13 of the ANKRD11 gene and results in an early termination signal 8 codons downstream of the frameshift introduced at Ala2265. This variant is predicted to generate a non-functional allele through either the expression of a truncated protein or a loss of ankyrin repeat domain containing 11 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 521294) that has been observed in many individuals affected by intellectual disability, epileptic dyskinetic encephalopathy, and/or KBG syndrome (PMID: 27605097, 34012832, 36446582, 38317675). This variant is present in 3 of 123718 alleles (0.0024%) in the gnomAD population dataset. Haploinsufficiency in ANKRD11 is a known mechanism of disease (PMID: 29565525). Based upon the evidence, we consider this a pathogenic variant. ACMG Criteria: PM2, PS4, PVS1

Mar 29, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ANKRD11 c.6792dup (p.Ala2265ArgfsTer8) variant has been reported as occurring de novo in at least one individual affected with KBG syndrome (Goldenberg A et al., PMID: 27605097). This variant has been reported in the ClinVar database as a germline pathogenic variant by eight submitters. This variant causes a frameshift by duplicating a single nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Additionally, other variants that introduce premature termination codons in this region have been described in affected individuals and are considered pathogenic (Goldenberg A et al., PMID: 27605097). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Sep 06, 2023

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.Ala2265Argfs*8) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 521294). This premature translational stop signal has been observed in individual(s) with KBG syndrome (PMID: 27605097). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.

Jun 20, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 16, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). However, the variant quality is low and allele frequency estimates may not be reliable. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521294 /PMID: 27605097 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

not provided

Pathogenic:3

Aug 03, 2022

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; This variant is associated with the following publications: (PMID: 27605097, 34012832)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Jun 02, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6792dupC (p.A2265Rfs*8) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a duplication of C at position 6792, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the CC allele has an overall frequency of 0.002% (3/123718) total alleles studied. The highest observed frequency was 0.03% (2/6560) of Ashkenazi Jewish alleles. The ANKRD11 p.A2265Rfs*8 alteration has been reported as a de novo finding in two unrelated individuals with features of KBG syndrome (Goldenberg, 2016; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic.

Rare genetic intellectual disability

Pathogenic:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Epilepsy

Pathogenic:1

Jun 18, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria applied: PVS1, PS4, PM2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over