NM_020987.5:c.9368A>G

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.9368A>G(p.Lys3123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.242 in 1,613,926 control chromosomes in the GnomAD database, including 51,397 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 0.19 ( 3381 hom., cov: 32)

Exomes 𝑓: 0.25 ( 48016 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.62

Publications

23 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=0.001493752).

BP6

Variant 10-60071513-T-C is Benign according to our data. Variant chr10-60071513-T-C is described in ClinVar as Benign. ClinVar VariationId is 128385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.9368A>G	p.Lys3123Arg	missense_variant	Exon 37 of 44	ENST00000280772.7	NP_066267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 link	c.9368A>G	p.Lys3123Arg	missense_variant	Exon 37 of 44	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28427

AN:

152056

Hom.:

3380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0490

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.0368

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.204

AC:

51224

AN:

251240

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.0441

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.0359

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.248

AC:

362857

AN:

1461752

Hom.:

48016

Cov.:

AF XY:

0.246

AC XY:

178891

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0402

AC:

1347

AN:

33472

American (AMR)

AF:

0.167

AC:

7466

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

5450

AN:

26130

East Asian (EAS)

AF:

0.0493

AC:

1957

AN:

39700

South Asian (SAS)

AF:

0.157

AC:

13576

AN:

86252

European-Finnish (FIN)

AF:

0.255

AC:

13632

AN:

53418

Middle Eastern (MID)

AF:

0.224

AC:

1291

AN:

5764

European-Non Finnish (NFE)

AF:

0.274

AC:

304381

AN:

1111916

Other (OTH)

AF:

0.228

AC:

13757

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

16486

32972

49457

65943

82429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9908

19816

29724

39632

49540

<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:

0.187

AC:

28431

AN:

152174

Hom.:

3381

Cov.:

AF XY:

0.187

AC XY:

13935

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0488

AC:

2029

AN:

41538

American (AMR)

AF:

0.214

AC:

3271

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

714

AN:

3468

East Asian (EAS)

AF:

0.0375

AC:

194

AN:

5178

South Asian (SAS)

AF:

0.160

AC:

770

AN:

4824

European-Finnish (FIN)

AF:

0.248

AC:

2630

AN:

10588

Middle Eastern (MID)

AF:

0.207

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.267

AC:

18134

AN:

67988

Other (OTH)

AF:

0.189

AC:

400

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1132

2264

3397

4529

5661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.242

Hom.:

20881

Bravo

AF:

0.177

TwinsUK

AF:

0.264

AC:

980

ALSPAC

AF:

0.290

AC:

1116

ESP6500AA

AF:

0.0513

AC:

226

ESP6500EA

AF:

0.261

AC:

2244

ExAC

AF:

0.202

AC:

24505

Asia WGS

AF:

0.0890

AC:

313

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. -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.094

DEOGEN2

Benign

0.23

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.11

PhyloP100

4.6

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.54

REVEL

Benign

0.094

Sift

Benign

0.81

Polyphen

0.0010

Vest4

0.18

MPC

0.54

ClinPred

0.0096

GERP RS

5.2

Varity_R

0.051

gMVP

0.15

Mutation Taster

=96/4

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