chr10-60071532-T-C

Position:

chr10-60071532-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_020987.5(ANK3):c.9349A>G(p.Ile3117Val) variant causes a missense change. The variant allele was found at a frequency of 0.0925 in 1,611,226 control chromosomes in the GnomAD database, including 7,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.072 ( 540 hom., cov: 32)

Exomes 𝑓: 0.095 ( 7375 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.21

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 -19 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=0.0015985668).

BP6

Variant 10-60071532-T-C is Benign according to our data. Variant chr10-60071532-T-C is described in ClinVar as [Benign]. Clinvar id is 128384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5 linkuse as main transcript	c.9349A>G	p.Ile3117Val	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.9349A>G	p.Ile3117Val	missense_variant	37/44	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.0717

AC:

10895

AN:

152032

Hom.:

540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0199

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0698

Gnomad ASJ

AF:

0.0574

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0774

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.0761

GnomAD3 exomes

AF:

0.0720

AC:

18059

AN:

250954

Hom.:

921

AF XY:

0.0724

AC XY:

9823

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0499

Gnomad ASJ exome

AF:

0.0611

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0210

Gnomad FIN exome

AF:

0.0820

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0955

GnomAD4 exome

AF:

0.0946

AC:

138095

AN:

1459076

Hom.:

7375

Cov.:

AF XY:

0.0929

AC XY:

67421

AN XY:

725810

show subpopulations

Gnomad4 AFR exome

AF:

0.0150

Gnomad4 AMR exome

AF:

0.0533

Gnomad4 ASJ exome

AF:

0.0628

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0214

Gnomad4 FIN exome

AF:

0.0857

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.0861

GnomAD4 genome

AF:

0.0716

AC:

10889

AN:

152150

Hom.:

540

Cov.:

AF XY:

0.0668

AC XY:

4972

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0199

Gnomad4 AMR

AF:

0.0698

Gnomad4 ASJ

AF:

0.0574

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0774

Gnomad4 NFE

AF:

0.112

Gnomad4 OTH

AF:

0.0754

Alfa

AF:

0.0969

Hom.:

460

Bravo

AF:

0.0687

TwinsUK

AF:

0.108

AC:

400

ALSPAC

AF:

0.0986

AC:

380

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.110

AC:

942

ExAC

AF:

0.0744

AC:

9027

Asia WGS

AF:

0.0160

AC:

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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. -

ANK3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 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

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.24

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.050

REVEL

Benign

0.090

Sift

Benign

0.31

Polyphen

0.0090

Vest4

0.099

MPC

0.12

ClinPred

0.010

GERP RS

5.2

Varity_R

0.079

gMVP

0.098

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