rs750428090

Variant names:

• chr4-113302770-A-G
• rs750428090
• NM_001148.6:c.2479A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001148.6(ANK2):​c.2479A>G​(p.Ile827Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,460,890 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: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.87

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030010402).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.2479A>G	p.Ile827Val	missense_variant	Exon 23 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.2479A>G	p.Ile827Val	missense_variant	Exon 23 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251416 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460890 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726840

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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jun 29, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I827V variant has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the I827V variant has been identified in one individual referred for LQTS testing at GeneDx. Nevertheless, I827V is classified in ClinVar as a variant of uncertain significance in association with LQTS by another clinical laboratory (ClinVar SCV000286238.1; Landrum et al., 2016). The I827V variant is a conservative amino acid substitution, and therefore is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved, and V827 is tolerated in several species. In silico analysis is inconsistent in its predictions; however, at least two models predict the variant is not damaging to the protein structure/function. -

Long QT syndrome Uncertain:1

Aug 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs750428090, gnomAD 0.01%). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 190525). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 827 of the ANK2 protein (p.Ile827Val). -

Cardiovascular phenotype Uncertain:1

Feb 10, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I827V variant (also known as c.2479A>G), located in coding exon 23 of the ANK2 gene, results from an A to G substitution at nucleotide position 2479. The isoleucine at codon 827 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.56
DEOGEN2	Benign	0.19	.;T;.;T;.;T;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T;D;D;T;D;D;D;T;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.030	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.4	.;.;.;.;N;N;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.31	N;N;N;N;N;N;N;.;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;.;B;B;.;.;B
Vest4		0.14, 0.13, 0.12, 0.19, 0.13
MVP		0.33
MPC		0.47
ClinPred		0.080	T
GERP RS		3.7
Varity_R		0.071
gMVP		0.24

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: rs750428090; hg19: chr4-114223926;