4-113134853-A-G

Variant names:

• chr4-113134853-A-G
• rs7697312
• NM_001148.6:c.85-39563A>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.85-39563A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 151,994 control chromosomes in the GnomAD database, including 37,923 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 (37923 hom., cov: 32)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.85-39563A>G		intron	N/A	NP_001139.3
	ANK2	NM_001386142.1		c.22-39563A>G		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.22-39563A>G		intron	N/A	NP_001373072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.85-39563A>G		intron	N/A	ENSP00000349588.4
	ANK2	ENST00000394537.7	TSL:1	c.85-39563A>G		intron	N/A	ENSP00000378044.3
	ANK2	ENST00000506722.5	TSL:1	c.22-39563A>G		intron	N/A	ENSP00000421067.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106752 AN: 151876 Hom.: 37883 Cov.: 32

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.671

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

GnomAD4 genome AF: 0.703 AC: 106858 AN: 151994 Hom.: 37923 Cov.: 32 AF XY: 0.702 AC XY: 52171 AN XY: 74310

African (AFR) AF: 0.759 AC: 31463 AN: 41458

American (AMR) AF: 0.720 AC: 10984 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1836 AN: 3466

East Asian (EAS) AF: 0.673 AC: 3479 AN: 5170

South Asian (SAS) AF: 0.671 AC: 3239 AN: 4826

European-Finnish (FIN) AF: 0.681 AC: 7193 AN: 10558

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46491 AN: 67944

Other (OTH) AF: 0.671 AC: 1417 AN: 2112

Alfa AF: 0.696 Hom.: 4378

Bravo AF: 0.708

Asia WGS AF: 0.664 AC: 2306 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.89
PhyloP100		-0.49
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: rs7697312; hg19: chr4-114056009;