10-60072226-G-T

Variant names:

• chr10-60072226-G-T
• rs11599164
• NM_020987.5:c.8655C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: 2.43
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability-hypotonia-spasticity-sleep disorder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• intellectual disability

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000232682 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.8655C>A	p.His2885Gln	missense_variant	Exon 37 of 44	ENST00000280772.7	NP_066267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.8655C>A	p.His2885Gln	missense_variant	Exon 37 of 44	1	NM_020987.5	ENSP00000280772.1

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

GnomAD2 exomes AF: 0.0720 AC: 17972 AN: 249760 AF XY: 0.0722

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 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

African (AFR) AF: 0.0150 AC: 501 AN: 33470

American (AMR) AF: 0.0542 AC: 2423 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1654 AN: 26126

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39692

South Asian (SAS) AF: 0.0213 AC: 1841 AN: 86238

European-Finnish (FIN) AF: 0.0854 AC: 4559 AN: 53390

Middle Eastern (MID) AF: 0.0784 AC: 452 AN: 5764

European-Non Finnish (NFE) AF: 0.109 AC: 121071 AN: 1111958

Other (OTH) AF: 0.0855 AC: 5160 AN: 60386

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

African (AFR) AF: 0.0198 AC: 820 AN: 41512

American (AMR) AF: 0.0726 AC: 1109 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 199 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4826

European-Finnish (FIN) AF: 0.0778 AC: 825 AN: 10602

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7635 AN: 68018

Other (OTH) AF: 0.0757 AC: 160 AN: 2114

Alfa AF: 0.0947 Hom.: 2613

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.13
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
PhyloP100		2.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.081
Sift	Uncertain	0.0090	D
Vest4		0.091
ClinPred		0.021	T
GERP RS		5.7
Varity_R		0.068
gMVP		0.096
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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