4-113092130-A-G

Variant names:

• chr4-113092130-A-G
• rs592670
• NM_001148.6:c.84+42318A>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+42318A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 152,102 control chromosomes in the GnomAD database, including 36,713 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 0.69 (36713 hom., cov: 33)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• Publications: 0 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 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+42318A>G		intron	N/A	NP_001139.3
	ANK2	NM_001386142.1		c.22-82286A>G		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.22-82286A>G		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+42318A>G		intron	N/A	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000394537.7	TSL:1	c.84+42318A>G		intron	N/A	ENSP00000378044.3	Q01484-2
	ANK2	ENST00000506722.5	TSL:1	c.22-82286A>G		intron	N/A	ENSP00000421067.1	Q01484-5

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105438 AN: 151984 Hom.: 36686 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.694 AC: 105508 AN: 152102 Hom.: 36713 Cov.: 33 AF XY: 0.691 AC XY: 51359 AN XY: 74338

African (AFR) AF: 0.718 AC: 29785 AN: 41492

American (AMR) AF: 0.595 AC: 9091 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2479 AN: 3472

East Asian (EAS) AF: 0.804 AC: 4169 AN: 5184

South Asian (SAS) AF: 0.730 AC: 3524 AN: 4826

European-Finnish (FIN) AF: 0.670 AC: 7059 AN: 10538

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47209 AN: 67984

Other (OTH) AF: 0.678 AC: 1432 AN: 2112

Alfa AF: 0.690 Hom.: 114864

Bravo AF: 0.691

Asia WGS AF: 0.728 AC: 2530 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		-0.15
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: rs592670; hg19: chr4-114013286;