rs12500579

Variant names:

• chr4-112934321-C-G
• rs12500579
• ENST00000506722.5:c.21+29807C>G

Variant summary

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

The ENST00000506722.5(ANK2):​c.21+29807C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,060 control chromosomes in the GnomAD database, including 2,050 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 0.12 (2050 hom., cov: 32)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.21+29807C>G		intron_variant	Intron 2 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.21+29807C>G		intron_variant	Intron 2 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+228104C>G		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.21+29807C>G		intron_variant	Intron 2 of 46	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.21+29807C>G		intron_variant	Intron 2 of 47			ENSP00000499982.1
ANK2	ENST00000673298.1	c.21+29807C>G		intron_variant	Intron 2 of 46			ENSP00000500245.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18908 AN: 151942 Hom.: 2037 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0946

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0387

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.125 AC: 18966 AN: 152060 Hom.: 2050 Cov.: 32 AF XY: 0.129 AC XY: 9610 AN XY: 74332

African (AFR) AF: 0.250 AC: 10381 AN: 41446

American (AMR) AF: 0.0949 AC: 1450 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0857 AC: 297 AN: 3466

East Asian (EAS) AF: 0.340 AC: 1760 AN: 5170

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4814

European-Finnish (FIN) AF: 0.0745 AC: 787 AN: 10564

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0387 AC: 2632 AN: 68002

Other (OTH) AF: 0.117 AC: 247 AN: 2114

Alfa AF: 0.0799 Hom.: 114

Bravo AF: 0.128

Asia WGS AF: 0.350 AC: 1214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.35
DANN	Benign	0.64
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: rs12500579; hg19: chr4-113855477; COSMIC: COSV72390483;