rs1554569481

Positions:

• chr4-113358129-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001148.6(ANK2):​c.9511T>G​(p.Ser3171Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.21

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.14245173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6	c.9511T>G	p.Ser3171Ala	missense_variant	38/46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.9511T>G	p.Ser3171Ala	missense_variant	38/46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 01, 2017

Homozygous: p.Ser3171Ala (c.9511T>G) in exon 38 of the ANK2 gene (NM_001148.4; chr4-114279285-T-G) SCICD Classification: variant of uncertain significance based on lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: 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 Exac browser, ANK2 is highly intolerant to loss of function variants but relatively tolerant of missense and synonymous variation. The fact that this variant is homozygous does not make it more likely to be pathogenic. Since the patient's parents are first cousins, we would expect them to share ~1/8 of their DNA. This is a variant they each passed down to the patient and may not have any effect on the ankyrin protein in the heterozygous or homozygous state. Case data (not including our patient): · ClinVar: not present · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed bypublished functional studies and their clinical significance is uncertain." Conservation data: The serine at codon 3171 is not conserved across species. Neighboring amino acids are not conserved. The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and alanine. Nearby pat -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 526946). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 3171 of the ANK2 protein (p.Ser3171Ala). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Uncertain	0.035	D
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.015	D;D;T
Sift4G	Benign	0.74	T;T;T
Vest4		0.28
MutPred		0.22		.;Gain of glycosylation at S3138 (P = 0.0063);.;
MVP		0.80
MPC		0.093
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.093
gMVP		0.041

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554569481; hg19: chr4-114279285;