4-112947451-T-G

Variant names:

• chr4-112947451-T-G
• rs7678728
• ENST00000506722.5:c.21+42937T>G

Variant summary

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

The NM_001386142.1(ANK2):​c.21+42937T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,926 control chromosomes in the GnomAD database, including 13,984 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 0.40 (13984 hom., cov: 32)
• Consequence: ANK2 NM_001386142.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• 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 = 0.626 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386142.1. 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_001386142.1		c.21+42937T>G		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.21+42937T>G		intron	N/A	NP_001373072.1	A0A5F9ZGZ1
	ANK2	NM_001386186.2		c.73-226965T>G		intron	N/A	NP_001373115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000506722.5	TSL:1	c.21+42937T>G		intron	N/A	ENSP00000421067.1	Q01484-5
	ANK2	ENST00000672209.1		c.21+42937T>G		intron	N/A	ENSP00000499982.1	A0A5F9ZH30
	ANK2	ENST00000673298.1		c.21+42937T>G		intron	N/A	ENSP00000500245.1	A0A5F9ZHE4

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60529 AN: 151808 Hom.: 13966 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.358

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

GnomAD4 genome AF: 0.399 AC: 60590 AN: 151926 Hom.: 13984 Cov.: 32 AF XY: 0.402 AC XY: 29840 AN XY: 74272

African (AFR) AF: 0.632 AC: 26176 AN: 41420

American (AMR) AF: 0.419 AC: 6393 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1013 AN: 3466

East Asian (EAS) AF: 0.469 AC: 2424 AN: 5164

South Asian (SAS) AF: 0.353 AC: 1698 AN: 4808

European-Finnish (FIN) AF: 0.358 AC: 3767 AN: 10524

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18008 AN: 67964

Other (OTH) AF: 0.356 AC: 751 AN: 2108

Alfa AF: 0.313 Hom.: 12168

Bravo AF: 0.418

Asia WGS AF: 0.419 AC: 1456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.47
PhyloP100		-1.3
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: rs7678728; hg19: chr4-113868607;