rs41283526

chr10-60145969-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_020987.5(ANK3):c.2615-6882A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 892,554 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (45 hom.)
• Consequence: ANK3 NM_020987.5 intron
• Scores: Splicing: ADA: 0.01046
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.07

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 10-60145969-T-C is Benign according to our data. Variant chr10-60145969-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 377141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00795 (1211/152286) while in subpopulation NFE AF= 0.0109 (741/68026). AF 95% confidence interval is 0.0102. There are 10 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.2615-6882A>G		intron_variant		ENST00000280772.7
ANK3	NM_001204404.2	c.2616A>G	p.Lys872=	splice_region_variant, synonymous_variant	24/44
ANK3	NM_001204403.2	c.2597-6882A>G		intron_variant
ANK3	NM_001320874.2	c.2615-6882A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.2615-6882A>G		intron_variant		1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1213 AN: 152168 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00762 AC: 1023 AN: 134260 Hom.: 7 AF XY: 0.00728 AC XY: 532 AN XY: 73116

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00450

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000623

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00950 AC: 7036 AN: 740268 Hom.: 45 Cov.: 10 AF XY: 0.00906 AC XY: 3525 AN XY: 389108

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.00518

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000648

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.00844

GnomAD4 genome AF: 0.00795 AC: 1211 AN: 152286 Hom.: 10 Cov.: 32 AF XY: 0.00809 AC XY: 602 AN XY: 74458

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0104 Hom.: 9

Bravo AF: 0.00686

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ANK3: BS1, BS2 -

ANK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2021

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.032
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

Publications

LitVar

Other links and lift over

dbSNP: rs41283526; hg19: chr10-61905727;