rs76793093

Positions:

• chr16-89279755-G-A
• chr16-89279755-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013275.6(ANKRD11):​c.6787C>T​(p.Pro2263Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,523,960 control chromosomes in the GnomAD database, including 1,391 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (150 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1241 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.306

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014477372).
• BP6: Variant 16-89279755-G-A is Benign according to our data. Variant chr16-89279755-G-A is described in ClinVar as [Benign]. Clinvar id is 380369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89279755-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.6787C>T	p.Pro2263Ser	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.6787C>T	p.Pro2263Ser	missense_variant	10/14
ANKRD11	NM_001256183.2	c.6787C>T	p.Pro2263Ser	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6787C>T	p.Pro2263Ser	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5121 AN: 152136 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0331 AC: 4156 AN: 125568 Hom.: 123 AF XY: 0.0313 AC XY: 2157 AN XY: 68946

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.00947

Gnomad EAS exome AF: 0.0649

Gnomad SAS exome AF: 0.00892

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0387 AC: 53029 AN: 1371706 Hom.: 1241 Cov.: 33 AF XY: 0.0376 AC XY: 25397 AN XY: 675234

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0648

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0336 AC: 5122 AN: 152254 Hom.: 150 Cov.: 32 AF XY: 0.0375 AC XY: 2788 AN XY: 74444

Gnomad4 AFR AF: 0.00727

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0217 Hom.: 17

Bravo AF: 0.0253

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.00467 AC: 14

ESP6500EA AF: 0.0189 AC: 121

ExAC AF: 0.0179 AC: 1784

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

KBG syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.95
DEOGEN2	Benign	0.067	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.065	N
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.040	N;N;.
REVEL	Benign	0.030
Sift	Benign	0.26	T;T;.
Sift4G	Benign	0.81	T;T;.
Polyphen		0.0020	B;B;B
Vest4		0.019
MPC		0.087
ClinPred		0.0046	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.022

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: rs76793093; hg19: chr16-89346163; COSMIC: COSV56368187; COSMIC: COSV56368187;