ENST00000506722.5:c.-40+16647G>A

Variant names:

• chr4-112834911-G-A
• rs1026089
• ENST00000506722.5:c.-40+16647G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000506722.5(ANK2):​c.-40+16647G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,002 control chromosomes in the GnomAD database, including 6,921 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 0.30 (6921 hom., cov: 32)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.-40+16647G>A		intron_variant	Intron 1 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.-40+16647G>A		intron_variant	Intron 1 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+128694G>A		intron_variant	Intron 1 of 46		NP_001373115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.-40+16647G>A		intron_variant	Intron 1 of 46	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-40+16647G>A		intron_variant	Intron 1 of 47			ENSP00000499982.1
ANK2	ENST00000673298.1	c.-40+16647G>A		intron_variant	Intron 1 of 46			ENSP00000500245.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45434 AN: 151884 Hom.: 6904 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.299 AC: 45490 AN: 152002 Hom.: 6921 Cov.: 32 AF XY: 0.301 AC XY: 22391 AN XY: 74280

African (AFR) AF: 0.274 AC: 11373 AN: 41458

American (AMR) AF: 0.332 AC: 5073 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3468

East Asian (EAS) AF: 0.346 AC: 1787 AN: 5168

South Asian (SAS) AF: 0.328 AC: 1582 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3566 AN: 10542

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20045 AN: 67952

Other (OTH) AF: 0.333 AC: 705 AN: 2114

Alfa AF: 0.282 Hom.: 790

Bravo AF: 0.300

Asia WGS AF: 0.388 AC: 1349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1026089; hg19: chr4-113756067;