10-60665366-C-T

Variant names:

• chr10-60665366-C-T
• rs10509136
• ENST00000373827.6:c.58-50142G>A

Variant summary

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

The NM_001204403.2(ANK3):​c.58-50142G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,168 control chromosomes in the GnomAD database, including 1,468 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 0.11 (1468 hom., cov: 32)
• Consequence: ANK3 NM_001204403.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142
• Publications: 0 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_001204403.2	c.58-50142G>A		intron_variant	Intron 1 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000373827.6	c.58-50142G>A		intron_variant	Intron 1 of 43	1		ENSP00000362933.2
ANK3	ENST00000510382.1	n.63-50142G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17458 AN: 152050 Hom.: 1460 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0997

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

GnomAD4 genome AF: 0.115 AC: 17479 AN: 152168 Hom.: 1468 Cov.: 32 AF XY: 0.121 AC XY: 8986 AN XY: 74400

African (AFR) AF: 0.0302 AC: 1253 AN: 41538

American (AMR) AF: 0.238 AC: 3640 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1387 AN: 5180

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4822

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10576

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7920 AN: 67986

Other (OTH) AF: 0.102 AC: 215 AN: 2108

Alfa AF: 0.125 Hom.: 910

Bravo AF: 0.118

Asia WGS AF: 0.255 AC: 884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.82
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10509136; hg19: chr10-62425124;