16-89279215-G-A

Variant names:

• chr16-89279215-G-A
• rs1555524861
• NM_013275.6:c.7327C>T

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.7327C>T​(p.Gln2443*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.99
• Publications: 0 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 16-89279215-G-A is Pathogenic according to our data. Variant chr16-89279215-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 522007.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	NM_013275.6	MANE Select	c.7327C>T	p.Gln2443*	stop_gained	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.7327C>T	p.Gln2443*	stop_gained	Exon 10 of 14	NP_001243111.1
	ANKRD11	NM_001256183.2		c.7327C>T	p.Gln2443*	stop_gained	Exon 9 of 13	NP_001243112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.7327C>T	p.Gln2443*	stop_gained	Exon 9 of 13	ENSP00000301030.4
	ANKRD11	ENST00000378330.7	TSL:1	c.7327C>T	p.Gln2443*	stop_gained	Exon 10 of 14	ENSP00000367581.2
	ANKRD11	ENST00000642600.2		c.7327C>T	p.Gln2443*	stop_gained	Exon 9 of 13	ENSP00000495226.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459948 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726286

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4376

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Pathogenic:2

Jul 25, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is present in gnomAD <0.001 for a dominant condition (v4: 1 heterozygote(s), 0 homozygote(s)); This variant has limited previous evidence of pathogenicity in unrelated individual(s). This variant has been classified as pathogenic by clinical laboratories in ClinVar. - Other NMD-predicted variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease; Loss of function is a known mechanism of disease in this gene and is associated with KBG syndrome (MIM#148050); Variants in this gene are known to have variable expressivity. Intrafamilial variability is commonly reported (PMID: 29258554); Parental origin of the variant is unresolved. Duo analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested.

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to the ClinVar database as Pathogenic but no details are available for independent assessment. The nucleotide change in ANKRD11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. Loss of function variants have been previously reported to be disease causing. Hence the above variant has been classified as Pathogenic.

Inborn genetic diseases Pathogenic:1

Aug 07, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.74
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555524861; hg19: chr16-89345623;