16-89268531-A-AGG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_013275.6(ANKRD11):c.7938_7939insCC(p.Phe2647ProfsTer39) 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 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: 0.706

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.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2650 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.7938_7939insCC	p.Phe2647ProfsTer39	frameshift_variant	13/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.7938_7939insCC	p.Phe2647ProfsTer39	frameshift_variant	14/14
ANKRD11	NM_001256183.2	c.7938_7939insCC	p.Phe2647ProfsTer39	frameshift_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.7938_7939insCC	p.Phe2647ProfsTer39	frameshift_variant	13/13	5	NM_013275.6	P1
	ENST00000602042.1	n.429_430dup		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 16, 2022

Variant summary: ANKRD11 c.7937_7938dupCC (p.Phe2647ProfsX39) causes a frameshift which results in an extension of the protein. The variant was absent in 153494 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7937_7938dupCC in individuals affected with KBG Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Protein extensions have not been reported to be associated with KBG Syndrome in HGMD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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: chr16-89334939;