rs115903343

Positions:

• chr10-60069928-T-G

Variant summary

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

The ENST00000280772.7(ANK3):​c.10953A>C​(p.Lys3651Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,014 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: ANK3 ENST00000280772.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.648

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 in gene, where missense usually causes diseases (based on misZ statistic), ANK3. . Gene score misZ 2.7937 (greater than the threshold 3.09). Trascript score misZ 5.3471 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, Tourette syndrome, intellectual disability-hypotonia-spasticity-sleep disorder syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019729137).
• BP6: Variant 10-60069928-T-G is Benign according to our data. Variant chr10-60069928-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 445527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1529/152280) while in subpopulation AFR AF= 0.0348 (1445/41560). AF 95% confidence interval is 0.0333. There are 29 homozygotes in gnomad4. There are 724 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.10953A>C	p.Lys3651Asn	missense_variant	37/44	ENST00000280772.7	NP_066267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.10953A>C	p.Lys3651Asn	missense_variant	37/44	1	NM_020987.5	ENSP00000280772

Frequencies

GnomAD3 genomes AF: 0.00998 AC: 1518 AN: 152162 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00290 AC: 727 AN: 251050 Hom.: 12 AF XY: 0.00204 AC XY: 277 AN XY: 135696

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1461734 Hom.: 19 Cov.: 34 AF XY: 0.000976 AC XY: 710 AN XY: 727162

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.0100 AC: 1529 AN: 152280 Hom.: 29 Cov.: 32 AF XY: 0.00972 AC XY: 724 AN XY: 74454

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00582 Hom.: 4

Bravo AF: 0.0115

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

ANK3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2020

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	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.069
Sift	Uncertain	0.0050	D
Polyphen		0.030	B
Vest4		0.057
MutPred		0.20		Loss of ubiquitination at K3651 (P = 3e-04);
MVP		0.46
MPC		0.17
ClinPred		0.030	T
GERP RS		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.63

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: rs115903343; hg19: chr10-61829686;