rs10821668

chr10-60071513-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.9368A>G(p.Lys3123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.242 in 1,613,926 control chromosomes in the GnomAD database, including 51,397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3381 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48016 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.62

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=0.001493752).
• BP6: Variant 10-60071513-T-C is Benign according to our data. Variant chr10-60071513-T-C is described in ClinVar as [Benign]. Clinvar id is 128385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.9368A>G	p.Lys3123Arg	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.9368A>G	p.Lys3123Arg	missense_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28427 AN: 152056 Hom.: 3380 Cov.: 32

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.204 AC: 51224 AN: 251240 Hom.: 6206 AF XY: 0.208 AC XY: 28279 AN XY: 135778

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0359

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.248 AC: 362857 AN: 1461752 Hom.: 48016 Cov.: 38 AF XY: 0.246 AC XY: 178891 AN XY: 727192

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.0493

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.187 AC: 28431 AN: 152174 Hom.: 3381 Cov.: 32 AF XY: 0.187 AC XY: 13935 AN XY: 74414

Gnomad4 AFR AF: 0.0488

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.189

Alfa AF: 0.249 Hom.: 12554

Bravo AF: 0.177

TwinsUK AF: 0.264 AC: 980

ALSPAC AF: 0.290 AC: 1116

ESP6500AA AF: 0.0513 AC: 226

ESP6500EA AF: 0.261 AC: 2244

ExAC AF: 0.202 AC: 24505

Asia WGS AF: 0.0890 AC: 313 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. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	23
Dann	Benign	0.094
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.11	N
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.094
Sift	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.18
MPC		0.54
ClinPred		0.0096	T
GERP RS		5.2
Varity_R		0.051
gMVP		0.15

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: rs10821668; hg19: chr10-61831271; COSMIC: COSV55051103; COSMIC: COSV55051103;