rs140463162

Positions:

chr10-60073926-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_020987.5(ANK3):c.6955G>A(p.Asp2319Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00327 in 1,613,922 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 23 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK3. . Gene score misZ 2.7937 (greater than the threshold 3.09). Trascript score misZ 5.3471 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, Tourette syndrome, intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050439835).

BP6

Variant 10-60073926-C-T is Benign according to our data. Variant chr10-60073926-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-60073926-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5 linkuse as main transcript	c.6955G>A	p.Asp2319Asn	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7 linkuse as main transcript	c.6955G>A	p.Asp2319Asn	missense_variant	37/44	1	NM_020987.5		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.00314

AC:

478

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00327

AC:

822

AN:

251024

Hom.:

AF XY:

0.00324

AC XY:

440

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00864

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00262

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00329

AC:

4807

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2279

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00853

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.0139

Gnomad4 NFE exome

AF:

0.00316

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.00314

AC:

478

AN:

152140

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.00318

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00264

Hom.:

Bravo

AF:

0.00201

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00277

AC:

336

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00207

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 12, 2016

- -

ANK3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Polyphen

0.99

Vest4

0.35

MVP

0.64

MPC

0.60

ClinPred

0.029

GERP RS

5.9

Varity_R

0.31

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over