dbSNP rs878855327: ANKRD11:p.Ala2265ProfsTer72 (chr16-89279749-CG-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_013275.6(ANKRD11):c.6792delC(p.Ala2265ProfsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANKRD11
NM_013275.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

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-CG-C is Pathogenic according to our data. Variant chr16-89279749-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 242348.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 link	c.6792delC	p.Ala2265ProfsTer72	frameshift_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4	Q6UB99
ANKRD11	NM_001256182.2 link	c.6792delC	p.Ala2265ProfsTer72	frameshift_variant	Exon 10 of 14		NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2 link	c.6792delC	p.Ala2265ProfsTer72	frameshift_variant	Exon 9 of 13		NP_001243112.1	Q6UB99

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10 link	c.6792delC	p.Ala2265ProfsTer72	frameshift_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4		Q6UB99

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1371814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

675452

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:

0.00

AC:

AN:

34004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4792

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071130

Other (OTH)

AF:

0.00

AC:

AN:

57116

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KBG syndrome

Pathogenic:2

Jun 09, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 26, 2021

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant located in exon 9 (of 13) of the ANKRD11 gene alters the wild type translational reading frame and is predicted to result in an absent or truncated protein product. A frameshift variant affecting the same codon and with identical predicted affect on the protein [c.6793delC (p.Ala2265Profs)] has been reported in a patient affected with moderate intellectual disability, seizures, hearing impairment, facial dysmorphism, myalgia, and abnormal biochemical findings (decreased Complex I & V, Complex III near 5% reference; See “additional file2: Table S1” of PMID: 28554332). The variant is absent from gnomAD(v3) database suggesting it is not a common benign allele in the populations represented in that database. Based on the available evidence, the de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant identified in the ANKRD11 gene is reported as Pathogenic. -

not provided

Pathogenic:1

Feb 13, 2024

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33149276) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.1

Mutation Taster

=1/199

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over