16-89280475-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013275.6(ANKRD11):c.6067G>C(p.Ala2023Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,602,602 control chromosomes in the GnomAD database, including 1,621 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2023S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 165 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1456 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.467

Publications

13 publications found

Variant links:

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

ANKRD11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017634332).

BP6

Variant 16-89280475-C-G is Benign according to our data. Variant chr16-89280475-C-G is described in ClinVar as Benign. ClinVar VariationId is 380368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6 link	c.6067G>C	p.Ala2023Pro	missense_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4	Q6UB99
ANKRD11	NM_001256182.2 link	c.6067G>C	p.Ala2023Pro	missense_variant	Exon 10 of 14		NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2 link	c.6067G>C	p.Ala2023Pro	missense_variant	Exon 9 of 13		NP_001243112.1	Q6UB99

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10 link	c.6067G>C	p.Ala2023Pro	missense_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4		Q6UB99

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6165

AN:

152152

Hom.:

165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0311

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.0645

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0380

Gnomad OTH

AF:

0.0321

GnomAD2 exomes

AF:

0.0456

AC:

9298

AN:

203938

AF XY:

0.0437

show subpopulations

Gnomad AFR exome

AF:

0.0386

Gnomad AMR exome

AF:

0.0332

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0784

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0415

Gnomad OTH exome

AF:

0.0489

GnomAD4 exome

AF:

0.0403

AC:

58437

AN:

1450332

Hom.:

1456

Cov.:

AF XY:

0.0391

AC XY:

28210

AN XY:

720908

show subpopulations

African (AFR)

AF:

0.0300

AC:

997

AN:

33240

American (AMR)

AF:

0.0307

AC:

1339

AN:

43666

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

282

AN:

25762

East Asian (EAS)

AF:

0.0665

AC:

2613

AN:

39322

South Asian (SAS)

AF:

0.0117

AC:

1002

AN:

85572

European-Finnish (FIN)

AF:

0.122

AC:

6220

AN:

51074

Middle Eastern (MID)

AF:

0.00792

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.0395

AC:

43761

AN:

1106484

Other (OTH)

AF:

0.0365

AC:

2180

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3449

6898

10348

13797

17246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1696

3392

5088

6784

8480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0405

AC:

6168

AN:

152270

Hom.:

165

Cov.:

AF XY:

0.0440

AC XY:

3277

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0311

AC:

1291

AN:

41578

American (AMR)

AF:

0.0265

AC:

406

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.0649

AC:

336

AN:

5180

South Asian (SAS)

AF:

0.0160

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.129

AC:

1370

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0380

AC:

2587

AN:

67996

Other (OTH)

AF:

0.0317

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

296

591

887

1182

1478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0210

Hom.:

Bravo

AF:

0.0331

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.0180

AC:

ESP6500EA

AF:

0.0308

AC:

203

ExAC

AF:

0.0395

AC:

4582

Asia WGS

AF:

0.0420

AC:

146

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 22, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KBG syndrome

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 19, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.9

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.078

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.61

.;.;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L

PhyloP100

0.47

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.39

N;N;.

REVEL

Benign

0.0090

Sift

Benign

0.27

T;T;.

Sift4G

Benign

0.30

T;T;.

Polyphen

0.45

B;B;B

Vest4

0.067

MPC

0.16

ClinPred

0.0016

GERP RS

0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.093

gMVP

0.088

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over