4-113088729-C-T

Variant names:

• chr4-113088729-C-T
• rs649022
• NM_001148.6:c.84+38917C>T

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+38917C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 151,934 control chromosomes in the GnomAD database, including 39,230 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 0.70 (39230 hom., cov: 31)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 3 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001148.6. 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
	ANK2	NM_001148.6	MANE Select	c.84+38917C>T		intron	N/A	NP_001139.3
	ANK2	NM_001386142.1		c.22-85687C>T		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.22-85687C>T		intron	N/A	NP_001373072.1	A0A5F9ZGZ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.84+38917C>T		intron	N/A	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000394537.7	TSL:1	c.84+38917C>T		intron	N/A	ENSP00000378044.3	Q01484-2
	ANK2	ENST00000506722.5	TSL:1	c.22-85687C>T		intron	N/A	ENSP00000421067.1	Q01484-5

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106942 AN: 151816 Hom.: 39166 Cov.: 31

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.705 AC: 107061 AN: 151934 Hom.: 39230 Cov.: 31 AF XY: 0.703 AC XY: 52191 AN XY: 74238

African (AFR) AF: 0.916 AC: 38018 AN: 41488

American (AMR) AF: 0.600 AC: 9146 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 2454 AN: 3468

East Asian (EAS) AF: 0.820 AC: 4220 AN: 5146

South Asian (SAS) AF: 0.741 AC: 3564 AN: 4808

European-Finnish (FIN) AF: 0.579 AC: 6102 AN: 10534

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41404 AN: 67928

Other (OTH) AF: 0.684 AC: 1441 AN: 2106

Alfa AF: 0.634 Hom.: 51397

Bravo AF: 0.717

Asia WGS AF: 0.769 AC: 2673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.37
PhyloP100		-0.16
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: rs649022; hg19: chr4-114009885;