rs28932171

Variant names:

Variant summary

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

The NM_020987.5(ANK3):c.9349A>G(p.Ile3117Val) variant causes a missense change. The variant allele was found at a frequency of 0.0925 in 1,611,226 control chromosomes in the GnomAD database, including 7,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 540 hom., cov: 32)

Exomes 𝑓: 0.095 ( 7375 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.21

Publications

18 publications found

Variant links:

Genes affected

ANK3 (HGNC:494): (ankyrin 3) Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ANK3 Gene-Disease associations (from GenCC):

intellectual disability-hypotonia-spasticity-sleep disorder syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
intellectual disability
Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ANK3 links:

ENSG00000232682 (HGNC:):

ENSG00000232682 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=0.0015985668).

BP6

Variant 10-60071532-T-C is Benign according to our data. Variant chr10-60071532-T-C is described in ClinVar as Benign. ClinVar VariationId is 128384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.9349A>G	p.Ile3117Val	missense_variant	Exon 37 of 44	ENST00000280772.7	NP_066267.2	Q12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 link	c.9349A>G	p.Ile3117Val	missense_variant	Exon 37 of 44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.0717

AC:

10895

AN:

152032

Hom.:

540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0199

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0698

Gnomad ASJ

AF:

0.0574

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0774

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.0761

GnomAD2 exomes

AF:

0.0720

AC:

18059

AN:

250954

AF XY:

0.0724

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0499

Gnomad ASJ exome

AF:

0.0611

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0820

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0955

GnomAD4 exome

AF:

0.0946

AC:

138095

AN:

1459076

Hom.:

7375

Cov.:

AF XY:

0.0929

AC XY:

67421

AN XY:

725810

show subpopulations

African (AFR)

AF:

0.0150

AC:

503

AN:

33470

American (AMR)

AF:

0.0533

AC:

2381

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.0628

AC:

1640

AN:

26096

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.0214

AC:

1848

AN:

86156

European-Finnish (FIN)

AF:

0.0857

AC:

4570

AN:

53298

Middle Eastern (MID)

AF:

0.0793

AC:

457

AN:

5762

European-Non Finnish (NFE)

AF:

0.109

AC:

121498

AN:

1109646

Other (OTH)

AF:

0.0861

AC:

5191

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

7578

15155

22733

30310

37888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4146

8292

12438

16584

20730

<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:

0.0716

AC:

10889

AN:

152150

Hom.:

540

Cov.:

AF XY:

0.0668

AC XY:

4972

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0199

AC:

826

AN:

41528

American (AMR)

AF:

0.0698

AC:

1067

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0574

AC:

199

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0168

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0774

AC:

819

AN:

10588

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7647

AN:

67976

Other (OTH)

AF:

0.0754

AC:

159

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

507

1014

1521

2028

2535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0859

Hom.:

466

Bravo

AF:

0.0687

TwinsUK

AF:

0.108

AC:

400

ALSPAC

AF:

0.0986

AC:

380

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.110

AC:

942

ExAC

AF:

0.0744

AC:

9027

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

ANK3-related disorder

Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.24

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

4.2

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.050

REVEL

Benign

0.090

Sift

Benign

0.31

Polyphen

0.0090

Vest4

0.099

MPC

0.12

ClinPred

0.010

GERP RS

5.2

Varity_R

0.079

gMVP

0.098

Mutation Taster

=91/9

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