10-60345018-T-C

Variant names:

• chr10-60345018-T-C
• rs4582919
• NM_020987.5:c.114+44407A>G

Variant summary

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

The NM_020987.5(ANK3):​c.114+44407A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,974 control chromosomes in the GnomAD database, including 19,714 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 0.50 (19714 hom., cov: 32)
• Consequence: ANK3 NM_020987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.114+44407A>G		intron_variant	Intron 1 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.64-65379A>G		intron_variant	Intron 1 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.114+44407A>G		intron_variant	Intron 1 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.97-65379A>G		intron_variant	Intron 2 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.114+44407A>G		intron_variant	Intron 1 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76248 AN: 151856 Hom.: 19700 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.505

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

GnomAD4 genome AF: 0.502 AC: 76302 AN: 151974 Hom.: 19714 Cov.: 32 AF XY: 0.512 AC XY: 38021 AN XY: 74274

African (AFR) AF: 0.395 AC: 16395 AN: 41460

American (AMR) AF: 0.553 AC: 8437 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1807 AN: 3470

East Asian (EAS) AF: 0.688 AC: 3545 AN: 5154

South Asian (SAS) AF: 0.604 AC: 2914 AN: 4822

European-Finnish (FIN) AF: 0.605 AC: 6382 AN: 10542

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35249 AN: 67946

Other (OTH) AF: 0.507 AC: 1070 AN: 2110

Alfa AF: 0.505 Hom.: 58450

Bravo AF: 0.490

Asia WGS AF: 0.625 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.060
DANN	Benign	0.44
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs4582919; hg19: chr10-62104776;