rs117475706

chr10-60075299-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_020987.5(ANK3):c.5582C>T(p.Thr1861Met) variant causes a missense change. The variant allele was found at a frequency of 0.00431 in 1,614,154 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1861T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3
• Conservation: PhyloP100: 5.50

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006896615).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00447 (6529/1461808) while in subpopulation NFE AF= 0.00545 (6057/1111972). AF 95% confidence interval is 0.00533. There are 17 homozygotes in gnomad4_exome. There are 3148 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.5582C>T	p.Thr1861Met	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.5582C>T	p.Thr1861Met	missense_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00259 AC: 647 AN: 250042 Hom.: 0 AF XY: 0.00239 AC XY: 323 AN XY: 135176

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00447 AC: 6529 AN: 1461808 Hom.: 17 Cov.: 35 AF XY: 0.00433 AC XY: 3148 AN XY: 727210

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00545

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00264 AC XY: 197 AN XY: 74494

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00401 Hom.: 2

Bravo AF: 0.00285

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 15, 2022	Functional studies proved missense was disruptive (PMID: 31451636). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ANK3: BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 24, 2016

- -

ANK3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2022

This variant is classified as likely 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	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.0038
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.080
Sift	Uncertain	0.0030	D
Polyphen		0.11	B
Vest4		0.17
MVP		0.59
MPC		0.36
ClinPred		0.032	T
GERP RS		4.7
Varity_R		0.094
gMVP		0.47

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: rs117475706; hg19: chr10-61835057;