10-60042719-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020987.5(ANK3):c.13106G>A(p.Arg4369Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00637 in 1,613,858 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4369W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (51 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.86

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=0.0039607286).
• BP6: Variant 10-60042719-C-T is Benign according to our data. Variant chr10-60042719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 434147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-60042719-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00519 (790/152090) while in subpopulation AMR AF= 0.00693 (106/15286). AF 95% confidence interval is 0.00618. There are 3 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.13106G>A	p.Arg4369Gln	missense_variant	43/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.13106G>A	p.Arg4369Gln	missense_variant	43/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 151972 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00573 AC: 1441 AN: 251412 Hom.: 10 AF XY: 0.00589 AC XY: 801 AN XY: 135886

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00552

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00649 AC: 9490 AN: 1461768 Hom.: 51 Cov.: 30 AF XY: 0.00658 AC XY: 4784 AN XY: 727194

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00580

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00680

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152090 Hom.: 3 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74372

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.00669

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00742 Hom.: 9

Bravo AF: 0.00539

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00544 AC: 660

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00824

EpiControl AF: 0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ANK3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 14, 2016

- -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

ANK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 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	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.76	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Uncertain	0.0013	D
MutationAssessor	Benign	1.0	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.0	N;N;N;D;N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.96	D;.;.;.;.;.
Vest4		0.60
MVP		0.68
MPC		0.63
ClinPred		0.048	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141939315; hg19: chr10-61802477;