rs144270555

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_020987.5(ANK3):c.6916A>G(p.Lys2306Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 3.93

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071793705).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000204 (31/152136) while in subpopulation AMR AF= 0.000851 (13/15278). AF 95% confidence interval is 0.000503. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.6916A>G	p.Lys2306Glu	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.6916A>G	p.Lys2306Glu	missense_variant	Exon 37 of 44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000175

AC:

AN:

250972

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000204

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2306 of the ANK3 protein (p.Lys2306Glu). This variant is present in population databases (rs144270555, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ANK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 434188). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANK3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 20, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANK3: PM2, PM3, BP4 -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Uncertain:1Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

3billion

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

not specified

Uncertain:1

May 19, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Unlikely to be causative of ANK3-related neurodevelopmental disorder (AD). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.017

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.0074

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.87

REVEL

Benign

0.098

Sift

Uncertain

0.0020

Polyphen

0.0030

Vest4

0.33

MVP

0.62

MPC

0.20

ClinPred

0.042

GERP RS

5.9

Varity_R

0.34

gMVP

0.24

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