rs2272230

Variant names:

• chr4-113339382-C-T
• rs2272230
• NM_001148.6:c.3893+60C>T

Variant summary

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

The NM_001148.6(ANK2):​c.3893+60C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,337,118 control chromosomes in the GnomAD database, including 14,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (5200 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9657 hom.)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226
• Publications: 4 publications found

Genes affected

ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. 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. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]

ANK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-113339382-C-T is Benign according to our data. Variant chr4-113339382-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.3893+60C>T		intron_variant	Intron 32 of 45	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.3893+60C>T		intron_variant	Intron 32 of 45	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30915 AN: 151928 Hom.: 5176 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.109 AC: 129364 AN: 1185072 Hom.: 9657 AF XY: 0.109 AC XY: 65767 AN XY: 603062

African (AFR) AF: 0.472 AC: 12944 AN: 27430

American (AMR) AF: 0.137 AC: 6066 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2454 AN: 24400

East Asian (EAS) AF: 0.124 AC: 4766 AN: 38330

South Asian (SAS) AF: 0.125 AC: 9976 AN: 80092

European-Finnish (FIN) AF: 0.0659 AC: 3441 AN: 52188

Middle Eastern (MID) AF: 0.165 AC: 850 AN: 5164

European-Non Finnish (NFE) AF: 0.0955 AC: 82329 AN: 861988

Other (OTH) AF: 0.127 AC: 6538 AN: 51306

GnomAD4 genome AF: 0.204 AC: 30983 AN: 152046 Hom.: 5200 Cov.: 32 AF XY: 0.199 AC XY: 14768 AN XY: 74334

African (AFR) AF: 0.464 AC: 19211 AN: 41446

American (AMR) AF: 0.148 AC: 2254 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.116 AC: 602 AN: 5172

South Asian (SAS) AF: 0.119 AC: 573 AN: 4826

European-Finnish (FIN) AF: 0.0627 AC: 662 AN: 10566

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6891 AN: 67974

Other (OTH) AF: 0.181 AC: 382 AN: 2114

Alfa AF: 0.131 Hom.: 7039

Bravo AF: 0.222

Asia WGS AF: 0.142 AC: 493 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.61
PhyloP100		-0.23
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: rs2272230; hg19: chr4-114260538;