chr10-60042584-C-A

Variant names:

• chr10-60042584-C-A
• rs2393603
• NM_020987.5:c.*19+88G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020987.5(ANK3):​c.*19+88G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,291,042 control chromosomes in the GnomAD database, including 365,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40090 hom., cov: 33)
  • Exomes 𝑓: 0.75 (325738 hom.)
• Consequence: ANK3 NM_020987.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.985
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-60042584-C-A is Benign according to our data. Variant chr10-60042584-C-A is described in ClinVar as Benign. ClinVar VariationId is 1192391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	NM_020987.5	MANE Select	c.*19+88G>T		intron	N/A	NP_066267.2
	ANK3	NM_001204404.2		c.*19+88G>T		intron	N/A	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.*19+88G>T		intron	N/A	NP_001307803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.*19+88G>T		intron	N/A	ENSP00000280772.1	Q12955-3
	ANK3	ENST00000373827.6	TSL:1	c.*19+88G>T		intron	N/A	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000355288.6	TSL:1	c.*19+88G>T		intron	N/A	ENSP00000347436.2	Q12955-6

Frequencies

GnomAD3 genomes AF: 0.723 AC: 109869 AN: 151930 Hom.: 40081 Cov.: 33

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.741

GnomAD4 exome AF: 0.754 AC: 859332 AN: 1138994 Hom.: 325738 AF XY: 0.754 AC XY: 431270 AN XY: 572262

African (AFR) AF: 0.652 AC: 16479 AN: 25288

American (AMR) AF: 0.572 AC: 17361 AN: 30354

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 15917 AN: 20204

East Asian (EAS) AF: 0.782 AC: 28871 AN: 36916

South Asian (SAS) AF: 0.712 AC: 47757 AN: 67050

European-Finnish (FIN) AF: 0.688 AC: 34138 AN: 49654

Middle Eastern (MID) AF: 0.745 AC: 3713 AN: 4984

European-Non Finnish (NFE) AF: 0.770 AC: 658465 AN: 855528

Other (OTH) AF: 0.747 AC: 36631 AN: 49016

GnomAD4 genome AF: 0.723 AC: 109920 AN: 152048 Hom.: 40090 Cov.: 33 AF XY: 0.722 AC XY: 53664 AN XY: 74298

African (AFR) AF: 0.650 AC: 26967 AN: 41464

American (AMR) AF: 0.677 AC: 10352 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2732 AN: 3468

East Asian (EAS) AF: 0.820 AC: 4237 AN: 5168

South Asian (SAS) AF: 0.723 AC: 3486 AN: 4822

European-Finnish (FIN) AF: 0.685 AC: 7225 AN: 10552

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.772 AC: 52477 AN: 67984

Other (OTH) AF: 0.742 AC: 1566 AN: 2110

Alfa AF: 0.753 Hom.: 121891

Bravo AF: 0.717

Asia WGS AF: 0.755 AC: 2626 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability-hypotonia-spasticity-sleep disorder syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.71
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2393603; hg19: chr10-61802342;