rs114937210

Positions:

• chr10-60278806-T-C

Variant summary

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

The NM_020987.5(ANK3):​c.382A>G​(p.Thr128Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,613,940 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.26

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=0.005452752).
• BP6: Variant 10-60278806-T-C is Benign according to our data. Variant chr10-60278806-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128369.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 = 0.0101 (1539/152264) while in subpopulation AFR AF= 0.0358 (1488/41546). AF 95% confidence interval is 0.0343. There are 43 homozygotes in gnomad4. There are 735 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.382A>G	p.Thr128Ala	missense_variant	4/44	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.331A>G	p.Thr111Ala	missense_variant	4/44		NP_001191333.1
ANK3	NM_001320874.2	c.382A>G	p.Thr128Ala	missense_variant	4/43		NP_001307803.1
ANK3	NM_001204403.2	c.364A>G	p.Thr122Ala	missense_variant	5/44		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.382A>G	p.Thr128Ala	missense_variant	4/44	1	NM_020987.5	ENSP00000280772

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1532 AN: 152146 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00262 AC: 657 AN: 251086 Hom.: 12 AF XY: 0.00170 AC XY: 231 AN XY: 135678

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00100 AC: 1461 AN: 1461676 Hom.: 28 Cov.: 31 AF XY: 0.000827 AC XY: 601 AN XY: 727146

Gnomad4 AFR exome AF: 0.0354

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152264 Hom.: 43 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74438

Gnomad4 AFR AF: 0.0358

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.0116

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2021

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	0.071
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.;T
Eigen	Benign	0.010
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.3	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.054	T;T;T;T
Sift4G	Benign	0.33	.;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.24
MVP		0.60
MPC		1.1
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.14
gMVP		0.18

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: rs114937210; hg19: chr10-62038564;