rs4834308

Variant names:

• chr4-112886970-A-C
• rs4834308
• ENST00000506722.5:c.-39-17485A>C

Variant summary

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

The ENST00000506722.5(ANK2):​c.-39-17485A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,168 control chromosomes in the GnomAD database, including 2,312 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 0.15 (2312 hom., cov: 32)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.-39-17485A>C		intron_variant	Intron 1 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.-39-17485A>C		intron_variant	Intron 1 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+180753A>C		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.-39-17485A>C		intron_variant	Intron 1 of 46	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-39-17485A>C		intron_variant	Intron 1 of 47			ENSP00000499982.1
ANK2	ENST00000673298.1	c.-39-17485A>C		intron_variant	Intron 1 of 46			ENSP00000500245.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23561 AN: 152050 Hom.: 2310 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.155 AC: 23560 AN: 152168 Hom.: 2312 Cov.: 32 AF XY: 0.160 AC XY: 11867 AN XY: 74400

African (AFR) AF: 0.0609 AC: 2531 AN: 41554

American (AMR) AF: 0.237 AC: 3629 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3470

East Asian (EAS) AF: 0.354 AC: 1831 AN: 5168

South Asian (SAS) AF: 0.204 AC: 985 AN: 4824

European-Finnish (FIN) AF: 0.223 AC: 2358 AN: 10584

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11561 AN: 67966

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.160 Hom.: 4922

Bravo AF: 0.155

Asia WGS AF: 0.274 AC: 949 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.40
PhyloP100		-0.054
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: rs4834308; hg19: chr4-113808126;