rs60520302

chr16-89280475-C-Achr16-89280475-C-Gchr16-89280475-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013275.6(ANKRD11):c.6067G>T(p.Ala2023Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,450,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2023P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.467

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043483526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.6067G>T	p.Ala2023Ser	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.6067G>T	p.Ala2023Ser	missense_variant	10/14
ANKRD11	NM_001256183.2	c.6067G>T	p.Ala2023Ser	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6067G>T	p.Ala2023Ser	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000196 AC: 4 AN: 203938 Hom.: 0 AF XY: 0.00000879 AC XY: 1 AN XY: 113748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000733

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.000204

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1450374 Hom.: 0 Cov.: 34 AF XY: 0.00000832 AC XY: 6 AN XY: 720934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KBG syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 31, 2022

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2023 of the ANKRD11 protein (p.Ala2023Ser). This variant is present in population databases (rs60520302, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.52
Dann	Benign	0.92
DEOGEN2	Benign	0.056	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.46	N;N;.
REVEL	Benign	0.031
Sift	Benign	0.69	T;T;.
Sift4G	Benign	0.79	T;T;.
Polyphen		0.052	B;B;B
Vest4		0.12
MutPred		0.15		Gain of glycosylation at A2023 (P = 6e-04);Gain of glycosylation at A2023 (P = 6e-04);Gain of glycosylation at A2023 (P = 6e-04);
MVP		0.26
MPC		0.079
ClinPred		0.027	T
GERP RS		0.21
Varity_R		0.083
gMVP		0.028

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

LitVar

Other links and lift over

dbSNP: rs60520302; hg19: chr16-89346883;