4-113102693-A-G

Variant names:

• chr4-113102693-A-G
• rs313956
• NM_001148.6:c.84+52881A>G

Variant summary

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

The NM_001148.6(ANK2):​c.84+52881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 152,162 control chromosomes in the GnomAD database, including 53,267 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 0.83 (53267 hom., cov: 31)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.84+52881A>G		intron_variant	Intron 1 of 45	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.84+52881A>G		intron_variant	Intron 1 of 45	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126689 AN: 152044 Hom.: 53208 Cov.: 31

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.818

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

GnomAD4 genome AF: 0.833 AC: 126808 AN: 152162 Hom.: 53267 Cov.: 31 AF XY: 0.833 AC XY: 61964 AN XY: 74378

African (AFR) AF: 0.932 AC: 38751 AN: 41558

American (AMR) AF: 0.856 AC: 13074 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2794 AN: 3472

East Asian (EAS) AF: 0.947 AC: 4892 AN: 5164

South Asian (SAS) AF: 0.787 AC: 3792 AN: 4816

European-Finnish (FIN) AF: 0.772 AC: 8170 AN: 10588

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52773 AN: 67970

Other (OTH) AF: 0.817 AC: 1729 AN: 2116

Alfa AF: 0.796 Hom.: 78659

Bravo AF: 0.846

Asia WGS AF: 0.829 AC: 2885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.4
DANN	Benign	0.52
PhyloP100		-0.47
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: rs313956; hg19: chr4-114023849;