16-89268581-T-TCCTGCACCTTCAGCTGCCACTC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_013275.6(ANKRD11):c.7888_7889insGAGTGGCAGCTGAAGGTGCAGG(p.Glu2630GlyfsTer127) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ANKRD11 NM_013275.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.013 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.7888_7889insGAGTGGCAGCTGAAGGTGCAGG	p.Glu2630GlyfsTer127	frameshift_variant	13/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.7888_7889insGAGTGGCAGCTGAAGGTGCAGG	p.Glu2630GlyfsTer127	frameshift_variant	14/14
ANKRD11	NM_001256183.2	c.7888_7889insGAGTGGCAGCTGAAGGTGCAGG	p.Glu2630GlyfsTer127	frameshift_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7888_7889insGAGTGGCAGCTGAAGGTGCAGG	p.Glu2630GlyfsTer127	frameshift_variant	13/13	5	NM_013275.6	P1
	ENST00000602042.1	n.480_501dup		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2019

Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein extension as the last 34 amino acids are lost and replaced with 126 incorrect amino acids; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89334989;