4-113089932-G-T

Variant names:

• chr4-113089932-G-T
• rs10029516
• NM_001148.6:c.84+40120G>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+40120G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 152,010 control chromosomes in the GnomAD database, including 17,566 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 0.47 (17566 hom., cov: 33)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.541
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 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+40120G>T		intron	N/A	NP_001139.3
	ANK2	NM_001386142.1		c.22-84484G>T		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.22-84484G>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+40120G>T		intron	N/A	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000394537.7	TSL:1	c.84+40120G>T		intron	N/A	ENSP00000378044.3	Q01484-2
	ANK2	ENST00000506722.5	TSL:1	c.22-84484G>T		intron	N/A	ENSP00000421067.1	Q01484-5

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72074 AN: 151892 Hom.: 17555 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.461

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

GnomAD4 genome AF: 0.474 AC: 72115 AN: 152010 Hom.: 17566 Cov.: 33 AF XY: 0.465 AC XY: 34566 AN XY: 74296

African (AFR) AF: 0.485 AC: 20100 AN: 41448

American (AMR) AF: 0.338 AC: 5166 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1544 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1068 AN: 5186

South Asian (SAS) AF: 0.489 AC: 2364 AN: 4832

European-Finnish (FIN) AF: 0.448 AC: 4721 AN: 10528

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35603 AN: 67944

Other (OTH) AF: 0.462 AC: 978 AN: 2116

Alfa AF: 0.493 Hom.: 28750

Bravo AF: 0.461

Asia WGS AF: 0.323 AC: 1125 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.54
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: rs10029516; hg19: chr4-114011088;