chr10-60074815-G-A

Variant names:

• chr10-60074815-G-A
• rs17208576
• NM_020987.5:c.6066C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020987.5(ANK3):​c.6066C>T​(p.Ala2022Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 1,613,714 control chromosomes in the GnomAD database, including 7,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (541 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7316 hom.)
• Consequence: ANK3 NM_020987.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.840
• Publications: 16 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)

ENSG00000232682 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-60074815-G-A is Benign according to our data. Variant chr10-60074815-G-A is described in ClinVar as Benign. ClinVar VariationId is 128373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020987.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	NM_020987.5	MANE Select	c.6066C>T	p.Ala2022Ala	synonymous	Exon 37 of 44	NP_066267.2
	ANK3	NM_001204404.2		c.4408+5722C>T		intron	N/A	NP_001191333.1
	ANK3	NM_001320874.2		c.4405+5722C>T		intron	N/A	NP_001307803.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.6066C>T	p.Ala2022Ala	synonymous	Exon 37 of 44	ENSP00000280772.1
	ANK3	ENST00000373827.6	TSL:1	c.4387+5722C>T		intron	N/A	ENSP00000362933.2
	ANK3	ENST00000355288.6	TSL:1	c.1807+5722C>T		intron	N/A	ENSP00000347436.2

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10923 AN: 152054 Hom.: 541 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0727

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0767

GnomAD2 exomes AF: 0.0720 AC: 18023 AN: 250472 AF XY: 0.0724

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0510

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0953

GnomAD4 exome AF: 0.0942 AC: 137697 AN: 1461542 Hom.: 7316 Cov.: 36 AF XY: 0.0925 AC XY: 67215 AN XY: 727040

African (AFR) AF: 0.0152 AC: 508 AN: 33460

American (AMR) AF: 0.0544 AC: 2429 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1655 AN: 26126

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39694

South Asian (SAS) AF: 0.0214 AC: 1847 AN: 86140

European-Finnish (FIN) AF: 0.0855 AC: 4565 AN: 53396

Middle Eastern (MID) AF: 0.0781 AC: 450 AN: 5760

European-Non Finnish (NFE) AF: 0.109 AC: 121075 AN: 1111900

Other (OTH) AF: 0.0855 AC: 5160 AN: 60386

GnomAD4 genome AF: 0.0717 AC: 10917 AN: 152172 Hom.: 541 Cov.: 32 AF XY: 0.0673 AC XY: 5002 AN XY: 74370

African (AFR) AF: 0.0199 AC: 827 AN: 41536

American (AMR) AF: 0.0727 AC: 1112 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4808

European-Finnish (FIN) AF: 0.0778 AC: 822 AN: 10566

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7625 AN: 67998

Other (OTH) AF: 0.0759 AC: 160 AN: 2108

Alfa AF: 0.0928 Hom.: 1410

Bravo AF: 0.0687

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.1
DANN	Benign	0.66
PhyloP100		-0.84
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: rs17208576; hg19: chr10-61834573; COSMIC: COSV55050214; COSMIC: COSV55050214;