chr10-60072347-C-T

Position:

chr10-60072347-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_020987.5(ANK3):c.8534G>A(p.Gly2845Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,816 control chromosomes in the GnomAD database, including 6 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.06

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 -8 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=0.009991497).

BP6

Variant 10-60072347-C-T is Benign according to our data. Variant chr10-60072347-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210176.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5 linkuse as main transcript	c.8534G>A	p.Gly2845Glu	missense_variant	37/44	ENST00000280772.7	NP_066267.2	Q12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 linkuse as main transcript	c.8534G>A	p.Gly2845Glu	missense_variant	37/44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00139

AC:

349

AN:

250394

Hom.:

AF XY:

0.00143

AC XY:

193

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00234

AC:

3417

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1666

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.000613

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00275

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152282

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00130

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ANK3: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 23, 2015

- -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ANK3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

This variant is classified as likely 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

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.013

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.2

REVEL

Benign

0.025

Sift

Uncertain

0.018

Polyphen

0.016

Vest4

0.20

MVP

0.49

MPC

0.71

ClinPred

0.019

GERP RS

3.9

Varity_R

0.13

gMVP

0.12

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