chr10-60070826-T-C

Position:

chr10-60070826-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_020987.5(ANK3):c.10055A>G(p.Glu3352Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,614,178 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 29 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.724

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=0.0064894557).

BP6

Variant 10-60070826-T-C is Benign according to our data. Variant chr10-60070826-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 210138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00464 (6785/1461802) while in subpopulation MID AF= 0.0161 (93/5768). AF 95% confidence interval is 0.0135. There are 29 homozygotes in gnomad4_exome. There are 3449 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5 linkuse as main transcript	c.10055A>G	p.Glu3352Gly	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.10055A>G	p.Glu3352Gly	missense_variant	37/44	1	NM_020987.5	ENSP00000280772		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

505

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00508

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00399

AC:

1002

AN:

251286

Hom.:

AF XY:

0.00431

AC XY:

586

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00554

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00464

AC:

6785

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3449

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00336

Gnomad4 ASJ exome

AF:

0.0117

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00320

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.00498

Gnomad4 OTH exome

AF:

0.00515

GnomAD4 genome

AF:

0.00331

AC:

505

AN:

152376

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

238

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00509

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00529

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00384

AC:

466

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00524

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ANK3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 16, 2019	- -

ANK3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2021

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

0.067

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

M_CAP

Benign

0.023

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

REVEL

Benign

0.019

Sift

Benign

0.13

Polyphen

0.018

Vest4

0.088

MVP

0.37

MPC

0.16

ClinPred

0.0050

GERP RS

1.8

Varity_R

0.054

gMVP

0.19

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