rs28932171

chr10-60071532-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.21

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK3
• 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	UniProt
ANK3	NM_020987.5	c.9349A>G	p.Ile3117Val	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.9349A>G	p.Ile3117Val	missense_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10895 AN: 152032 Hom.: 540 Cov.: 32

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

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.: 41 AF XY: 0.0929 AC XY: 67421 AN XY: 725810

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.: 32 AF XY: 0.0668 AC XY: 4972 AN XY: 74382

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: 85

ESP6500EA AF: 0.110 AC: 942

ExAC AF: 0.0744 AC: 9027

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Benign	0.85
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.74	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.090
Sift	Benign	0.31	T
Polyphen		0.0090	B
Vest4		0.099
MPC		0.12
ClinPred		0.010	T
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

Other links and lift over

dbSNP: rs28932171; hg19: chr10-61831290; COSMIC: COSV55062301; COSMIC: COSV55062301;