rs1555525115

Positions:

• chr16-89279566-CCTTCGGGG-C
• chr16-89279566-CCTTCGGGG-CCTTCGGGGCTTCGGGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_013275.6(ANKRD11):​c.6968_6975del​(p.Ala2323GlyfsTer206) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.82

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]

ACMG classification

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 16-89279566-CCTTCGGGG-C is Pathogenic according to our data. Variant chr16-89279566-CCTTCGGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 546454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89279566-CCTTCGGGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.6968_6975del	p.Ala2323GlyfsTer206	frameshift_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.6968_6975del	p.Ala2323GlyfsTer206	frameshift_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.6968_6975del	p.Ala2323GlyfsTer206	frameshift_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6968_6975del	p.Ala2323GlyfsTer206	frameshift_variant	9/13	5	NM_013275.6	ENSP00000301030	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2024	The p.Ala2323GlyfsX206 variant in ANKRD11 has been reported in at least 3 individuals with KBG syndrome, including 2 de novo occurrences (Carraro 2019 PMID: 31144778, Martinez-Cayuelas 2023 PMID: 36446582, ClinVar SCV: SCV000999362.1). It was also confirmed to be de novo by trio whole genome sequencing in a female with mild intellectual disability, short stature, short 5th digits, and dental abnormalities by the Broad Institute Rare Genomes Project. It was absent from large population studies, but has been reported in ClinVar (Variation ID 546454). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2323 and leads to a premature termination codon 206 amino acids downstream. Loss of function of the ANKRD11 gene is an established disease mechanism in autosomal dominant KBG syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant KBG syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 22, 2022	This sequence change creates a premature translational stop signal (p.Ala2323Glyfs*206) 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 variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. ClinVar contains an entry for this variant (Variation ID: 546454). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2023	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31144778, 31209962) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555525115; hg19: chr16-89345974;