4-113356135-G-A

Position:

• chr4-113356135-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001148.6(ANK2):​c.7517G>A​(p.Arg2506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R2506R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK2. . Gene score misZ 1.9641 (greater than the threshold 3.09). Trascript score misZ 4.2513 (greater than threshold 3.09). GenCC has associacion of gene with heart conduction disease, Brugada syndrome, long QT syndrome, complex neurodevelopmental disorder, cardiac arrhythmia, ankyrin-B-related, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37661213).
• BS2: High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.7517G>A	p.Arg2506Gln	missense_variant	38/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.7517G>A	p.Arg2506Gln	missense_variant	38/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250578 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135392

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461834 Hom.: 0 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 05, 2017	We have seen this variant in an adult with familial atrial fibrillation in our center. Testing done by Invitae. p.Arg2506Gln (c.7517G>A) in exon 38 of the ANK2 gene (NM_001148.4) Chromosome position 4:114277291 G / A Given the lack of case data and the presence in gnomAD, with an elevated allele frequency in individuals of Ashkenazi Jewish descent, we consider this a variant of uncertain significance, probably benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). ANK2: The ANK2 gene encodes ankyrin-2 (aka ankyrin-B), which links integral membrane proteins to the underlying spectrin-actin cytoskeleton and plays a role in signaling and membrane protein trafficking and regulation. Mohler et al (2003) first proposed a link between ANK2 and long QT syndrome. A missense variant in ANK2 co-segregated with disease in 24 affected members of a large French kindred. They had a mixed phenotype of long QT syndrome, sinus node dysfunction and atrial fibrillation, which has been labeled long QT type 4. Inheritance was autosomal dominant. Sinus node dysfunction was detectable in utero while atrial fibrillation was only observed in adulthood. Mice heterozygous for a null variant in ANK2 were shown to be haploinsufficient for ankyrin-2 and to have arrhythmias similar to those seen in the human patients. In vitro studies revealed disruption of the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1, 4, 5- triphosphate receptors. Altered calcium signaling was also observed and was considered the rationale for arrhythmia. Additional cases of long QT and other arrhythmic phenotypes associated with ANK2 have since been reported (see Smith et al 2012 for review). Cunha et al (2011) provided a summary atrial fibrillation in families with ANK2 variants: "We identified a high incidence of AF in ANK2 mutation-positive probands. Probands harboring ANK2 loss-of-function alleles displayed early onset AF, commonly progressing to permanent AF.9, 13, 14 In one large kindred (74 members), 13 of 25 ANK2 loss-of-function variant carriers (phenotypes previously mapped to ANK2, Zmax=7.059) displayed AF (mean onset 40 ±18 years, 5 paroxysmal, 8 permanent), whereas non-carriers were asymptomatic.Only two individuals were non-penetrant for atrial phenotypes. The others had AF, AF with sinus node dysfunction, or sinus node dysfunction alone. In an unrelated large family, 20/36 individuals were positive for the ANK2 disease allele (maximal LOD score was for marker D4S1616; linkage Zmax=5.9, ?=0), and 3 of 20 disease allele carriers displayed AF (mean onset 48 ±12 years, two paroxysmal, 1 permanent), while thirteen displayed sinus node disease requiring pacemaker implantation (mean age for implantation 30±18 years12). Only four individuals were non-penetrant for atrial phenotypes." (see Cunha et al 2011 for cited references). Per the lab report and our searches, the variant has not been reported in association with disease to date. It is not present in ClinVar as of 4/4/2017. There are no other variants at or near this codon reported as pathogenic in ClinVar as of 4/4/2017. Per the Invitae lab report: "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably"; Align-GVGD: "Class C0")." This is a nonconservative amino acid change, from a positively-charged Arginine to a polar Glutamine. The Arginine at this location is conserved across all mammals, and across all other vertebrates we have information for except for fish, in which it varies widely. The variant was reported online in 15 of 138,135 individuals in the in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Located in exon 38, which is reported as being expressed in a brain-specific transcript (Otto et al, 1991; Cunha et al, 2008; Wu et al, 2015); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#406493; Landrum et al., 2016) -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2506 of the ANK2 protein (p.Arg2506Gln). This variant is present in population databases (rs780131495, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 406493). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.85	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.21	T;T
Vest4		0.47
MVP		0.75
MPC		0.48
ClinPred		0.39	T
GERP RS		6.0
Varity_R		0.29
gMVP		0.079

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

Publications

LitVar

Other links and lift over

dbSNP: rs780131495; hg19: chr4-114277291;