4-113079800-T-C

Variant names:

• chr4-113079800-T-C
• rs7694725
• NM_001148.6:c.84+29988T>C

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+29988T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 151,948 control chromosomes in the GnomAD database, including 44,382 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 0.76 (44382 hom., cov: 31)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.900
• Publications: 13 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.84+29988T>C		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+29988T>C		intron_variant	Intron 1 of 45	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115675 AN: 151830 Hom.: 44369 Cov.: 31

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.785

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

GnomAD4 genome AF: 0.762 AC: 115742 AN: 151948 Hom.: 44382 Cov.: 31 AF XY: 0.755 AC XY: 56059 AN XY: 74246

African (AFR) AF: 0.714 AC: 29553 AN: 41408

American (AMR) AF: 0.763 AC: 11650 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2574 AN: 3472

East Asian (EAS) AF: 0.510 AC: 2632 AN: 5164

South Asian (SAS) AF: 0.758 AC: 3644 AN: 4808

European-Finnish (FIN) AF: 0.721 AC: 7589 AN: 10524

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.816 AC: 55513 AN: 67994

Other (OTH) AF: 0.783 AC: 1655 AN: 2114

Alfa AF: 0.794 Hom.: 82960

Bravo AF: 0.758

Asia WGS AF: 0.635 AC: 2208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.1
DANN	Benign	0.58
PhyloP100		0.90
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: rs7694725; hg19: chr4-114000956;