NM_020987.5:c.10055A>G

Variant names:

Variant summary

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

The NM_020987.5(ANK3):c.10055A>G(p.Glu3352Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,614,178 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 29 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.724

Publications

11 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=0.0064894557).

BP6

Variant 10-60070826-T-C is Benign according to our data. Variant chr10-60070826-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210138.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 = 0.00331 (505/152376) while in subpopulation NFE AF = 0.00509 (346/68038). AF 95% confidence interval is 0.00464. There are 2 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.10055A>G	p.Glu3352Gly	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.10055A>G	p.Glu3352Gly	missense_variant	Exon 37 of 44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

505

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00508

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00399

AC:

1002

AN:

251286

AF XY:

0.00431

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00554

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00464

AC:

6785

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3449

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33458

American (AMR)

AF:

0.00336

AC:

150

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

306

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00320

AC:

276

AN:

86250

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00498

AC:

5539

AN:

1111984

Other (OTH)

AF:

0.00515

AC:

311

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

472

944

1416

1888

2360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<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:

0.00331

AC:

505

AN:

152376

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

238

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

41594

American (AMR)

AF:

0.00327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00509

AC:

346

AN:

68038

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

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:

0.00503

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00384

AC:

466

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00524

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANK3: BP4, BS2 -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 16, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ANK3-related disorder

Benign:1

Sep 20, 2021

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

0.067

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

M_CAP

Benign

0.023

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.72

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

REVEL

Benign

0.019

Sift

Benign

0.13

Polyphen

0.018

Vest4

0.088

MVP

0.37

MPC

0.16

ClinPred

0.0050

GERP RS

1.8

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.054

gMVP

0.19

Mutation Taster

=97/3

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

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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