Genetic Variant ANKRD11:p.Ala2266Val (chr16-89279745-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013275.6(ANKRD11):c.6797C>T(p.Ala2266Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,525,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2266A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.69

Publications

1 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: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, 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=0.014288813).

BP6

Variant 16-89279745-G-A is Benign according to our data. Variant chr16-89279745-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000329 (50/152144) while in subpopulation NFE AF = 0.000662 (45/68000). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD11	NM_013275.6	MANE Select	c.6797C>T	p.Ala2266Val	missense	Exon 9 of 13	NP_037407.4
ANKRD11	NM_001256182.2		c.6797C>T	p.Ala2266Val	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2		c.6797C>T	p.Ala2266Val	missense	Exon 9 of 13	NP_001243112.1	Q6UB99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.6797C>T	p.Ala2266Val	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
ANKRD11	ENST00000378330.7	TSL:1	c.6797C>T	p.Ala2266Val	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
ANKRD11	ENST00000642600.2		c.6797C>T	p.Ala2266Val	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000291

AC:

AN:

127174

AF XY:

0.000300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000419

Gnomad ASJ exome

AF:

0.000148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000722

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000409

AC:

561

AN:

1373142

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

292

AN XY:

676194

show subpopulations

African (AFR)

AF:

0.0000636

AC:

AN:

31428

American (AMR)

AF:

0.0000568

AC:

AN:

35230

Ashkenazi Jewish (ASJ)

AF:

0.0000833

AC:

AN:

24024

East Asian (EAS)

AF:

0.00

AC:

AN:

35890

South Asian (SAS)

AF:

0.00

AC:

AN:

78678

European-Finnish (FIN)

AF:

0.0000882

AC:

AN:

34000

Middle Eastern (MID)

AF:

0.000209

AC:

AN:

4792

European-Non Finnish (NFE)

AF:

0.000504

AC:

540

AN:

1071968

Other (OTH)

AF:

0.000193

AC:

AN:

57132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68000

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000359

Hom.:

Bravo

AF:

0.000295

ExAC

AF:

0.000185

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

ANKRD11-related disorder (1)

Inborn genetic diseases (1)

KBG syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.8

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.075

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.38

M_CAP

Benign

0.045

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

2.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.77

REVEL

Benign

0.022

Sift

Benign

0.098

Sift4G

Benign

0.54

Polyphen

0.0070

Vest4

0.098

MutPred

0.19

Gain of sheet (P = 0.0101)

MVP

0.21

MPC

0.086

ClinPred

0.022

GERP RS

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.034

gMVP

0.023

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over