NM_020987.5:c.898-8780G>A

Variant names:

• chr10-60222290-C-T
• rs10994257
• NM_020987.5:c.898-8780G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020987.5(ANK3):​c.898-8780G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,944 control chromosomes in the GnomAD database, including 6,282 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6282 hom., cov: 31)
• Consequence: ANK3 NM_020987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.261
• Publications: 5 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.898-8780G>A		intron_variant	Intron 8 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.847-8780G>A		intron_variant	Intron 8 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.898-8780G>A		intron_variant	Intron 8 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.880-8780G>A		intron_variant	Intron 9 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.898-8780G>A		intron_variant	Intron 8 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40499 AN: 151826 Hom.: 6289 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40480 AN: 151944 Hom.: 6282 Cov.: 31 AF XY: 0.271 AC XY: 20086 AN XY: 74244

African (AFR) AF: 0.110 AC: 4576 AN: 41476

American (AMR) AF: 0.258 AC: 3942 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1389 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2434 AN: 5148

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4816

European-Finnish (FIN) AF: 0.372 AC: 3916 AN: 10540

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21657 AN: 67932

Other (OTH) AF: 0.294 AC: 620 AN: 2108

Alfa AF: 0.298 Hom.: 3953

Bravo AF: 0.253

Asia WGS AF: 0.354 AC: 1229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.4
DANN	Benign	0.60
PhyloP100		0.26
Mutation Taster		=98/2	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: rs10994257; hg19: chr10-61982048;