rs10821668

Positions:

chr10-60071513-T-C

Variant summary

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

The ENST00000280772.7(ANK3):c.9368A>G(p.Lys3123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.242 in 1,613,926 control chromosomes in the GnomAD database, including 51,397 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 (★★).

Frequency

Genomes: 𝑓 0.19 ( 3381 hom., cov: 32)

Exomes 𝑓: 0.25 ( 48016 hom. )

Consequence

ANK3
ENST00000280772.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.62

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=0.001493752).

BP6

Variant 10-60071513-T-C is Benign according to our data. Variant chr10-60071513-T-C is described in ClinVar as [Benign]. Clinvar id is 128385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 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.9368A>G	p.Lys3123Arg	missense_variant	37/44	ENST00000280772.7	NP_066267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 linkuse as main transcript	c.9368A>G	p.Lys3123Arg	missense_variant	37/44	1	NM_020987.5	ENSP00000280772		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28427

AN:

152056

Hom.:

3380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0490

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.0368

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.204

AC:

51224

AN:

251240

Hom.:

6206

AF XY:

0.208

AC XY:

28279

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.0441

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.0359

Gnomad SAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.248

AC:

362857

AN:

1461752

Hom.:

48016

Cov.:

AF XY:

0.246

AC XY:

178891

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0402

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.209

Gnomad4 EAS exome

AF:

0.0493

Gnomad4 SAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.255

Gnomad4 NFE exome

AF:

0.274

Gnomad4 OTH exome

AF:

0.228

GnomAD4 genome

AF:

0.187

AC:

28431

AN:

152174

Hom.:

3381

Cov.:

AF XY:

0.187

AC XY:

13935

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0488

Gnomad4 AMR

AF:

0.214

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.0375

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.248

Gnomad4 NFE

AF:

0.267

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.249

Hom.:

12554

Bravo

AF:

0.177

TwinsUK

AF:

0.264

AC:

980

ALSPAC

AF:

0.290

AC:

1116

ESP6500AA

AF:

0.0513

AC:

226

ESP6500EA

AF:

0.261

AC:

2244

ExAC

AF:

0.202

AC:

24505

Asia WGS

AF:

0.0890

AC:

313

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.094

DEOGEN2

Benign

0.23

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.11

MutationTaster

Benign

0.99

P;P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.54

REVEL

Benign

0.094

Sift

Benign

0.81

Polyphen

0.0010

Vest4

0.18

MPC

0.54

ClinPred

0.0096

GERP RS

5.2

Varity_R

0.051

gMVP

0.15

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