16-89279749-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_013275.6(ANKRD11):​c.6792_6793insC​(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 (★★). 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:9

Conservation

PhyloP100: -3.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 521294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ANKRD11NM_013275.6 linkuse as main transcriptc.6792_6793insC p.Ala2265ArgfsTer8 frameshift_variant 9/13 ENST00000301030.10 NP_037407.4
ANKRD11NM_001256182.2 linkuse as main transcriptc.6792_6793insC p.Ala2265ArgfsTer8 frameshift_variant 10/14 NP_001243111.1
ANKRD11NM_001256183.2 linkuse as main transcriptc.6792_6793insC p.Ala2265ArgfsTer8 frameshift_variant 9/13 NP_001243112.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ANKRD11ENST00000301030.10 linkuse as main transcriptc.6792_6793insC p.Ala2265ArgfsTer8 frameshift_variant 9/135 NM_013275.6 ENSP00000301030 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.29e-7
AC:
1
AN:
1371808
Hom.:
0
Cov.:
33
AF XY:
0.00000148
AC XY:
1
AN XY:
675444
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000294
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

KBG syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJun 20, 2022- -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Frameshift variant is 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 without evidence for the classification (ClinVar ID: VCV000521294 / PMID: 27605097). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 06, 2023This 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). 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. This premature translational stop signal has been observed in individual(s) with KBG syndrome (PMID: 27605097). ClinVar contains an entry for this variant (Variation ID: 521294). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisMar 29, 2024The 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. -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 03, 2022Frameshift 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) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 02, 2023The 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
Pathogenic, no assertion criteria providedclinical testingService de Génétique Moléculaire, Hôpital Robert Debré-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs878855327; hg19: chr16-89346157; API