rs11599164

chr10-60072226-G-T

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.8655C>A(p.His2885Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 1,613,942 control chromosomes in the GnomAD database, including 7,869 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 (546 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7323 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.43

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=0.001482755).
• BP6: Variant 10-60072226-G-T is Benign according to our data. Variant chr10-60072226-G-T is described in ClinVar as [Benign]. Clinvar id is 128379.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.8655C>A	p.His2885Gln	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.8655C>A	p.His2885Gln	missense_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10926 AN: 152092 Hom.: 546 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0574

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0765

GnomAD3 exomes AF: 0.0720 AC: 17972 AN: 249760 Hom.: 905 AF XY: 0.0722 AC XY: 9770 AN XY: 135354

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0509

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0957

GnomAD4 exome AF: 0.0942 AC: 137669 AN: 1461732 Hom.: 7323 Cov.: 36 AF XY: 0.0924 AC XY: 67209 AN XY: 727174

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.0542

Gnomad4 ASJ exome AF: 0.0633

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.0854

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0855

GnomAD4 genome AF: 0.0717 AC: 10920 AN: 152210 Hom.: 546 Cov.: 32 AF XY: 0.0673 AC XY: 5010 AN XY: 74426

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0726

Gnomad4 ASJ AF: 0.0574

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.0778

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0757

Alfa AF: 0.0997 Hom.: 2056

Bravo AF: 0.0687

TwinsUK AF: 0.108 AC: 401

ALSPAC AF: 0.0983 AC: 379

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.109 AC: 934

ExAC AF: 0.0741 AC: 8990

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	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	20
Dann	Benign	0.92
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.081
Sift	Uncertain	0.0090	D
Polyphen		0.0030	B
Vest4		0.091
MutPred		0.096		Loss of catalytic residue at H2885 (P = 0.1063);
MPC		0.14
ClinPred		0.021	T
GERP RS		5.7
Varity_R		0.068
gMVP		0.096

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: rs11599164; hg19: chr10-61831984; COSMIC: COSV55057585; COSMIC: COSV55057585;