4-113345966-G-T

Variant names:

• chr4-113345966-G-T
• rs34591340
• NM_001148.6:c.4315G>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001148.6(ANK2):​c.4315G>T​(p.Gly1439Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,736 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3 O:1
• Conservation: PhyloP100: 2.89

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18178931).
• BP6: Variant 4-113345966-G-T is Benign according to our data. Variant chr4-113345966-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=6, not_provided=1}. Variant chr4-113345966-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000223 (34/152300) while in subpopulation NFE AF= 0.000397 (27/68024). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.4315G>T	p.Gly1439Cys	missense_variant	Exon 35 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.4315G>T	p.Gly1439Cys	missense_variant	Exon 35 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000397

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000283 AC: 71 AN: 251232 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135760

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000332 AC: 485 AN: 1461436 Hom.: 0 Cov.: 33 AF XY: 0.000330 AC XY: 240 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related Uncertain:3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANK2 NM_001148.4 exon 35 p.Gly1439Cys (c.4315G>T): This variant has been reported in the literature in at least 1 individual with HCM (Lopes 2015 PMID:25351510) as well as at least 2 individuals with a clinical suspicion of Long QT syndrome (Lieve 2013 PMID:23631430, Mullally 2013 PMID:23174487). This variant is present in 64/126500 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs34591340). This variant is present in ClinVar (Variation ID:67606). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies involving cardiomyocytes suggest that this variant may not impact the protein and displays properties similar to wild-type (Mohler 2007 PMID:17242276). Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (OMIM, PMID:12571597, PMID:15178757, PMID:17242276.) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. Limited evidence (PMID:26230511). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine (exon 35). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition: 0.0002795 (79 het, 0 hom). (P) 0309 An alternative amino acid change at the same position has been observed in gnomAD p.(Gly1439Asp): 0.000004 (1 het, 0 hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Major change. High conservation. (N) 0600 - Variant is located in an annotated domain or motif. UPA domain (NCBI_Conserved Domains, (N) 0704 - Comparable variant has low previous evidence for pathogenicity. NM_ 001148.4(ANK2):c.4315G>A; Gly1439Ser: considered Likely pathogenic in 1 patient with atrial fibrillation (PMID: 30276209). (P) 0808 - Previous reports of pathogenicity are conflicting. ClinVar: 5x VUS, 2x Likely benign, 1x benign, 1 not provided, with most recent submissions and evaluations tending towards benign/ likely benign. LOVD3: Likely benign x1 (VKGL Data sharing initiative, Netherlands). Earlier publications indicate an association with LQTS (PMID: 23174487, PMID: 28988457). However, more recent reports suggest is a VUS, with not enough evidence, or a VUS, likely benign (PMID: 28589536, PMID: 31638414, respectively. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1004 - Moderate functional evidence supporting normal protein function. PMID:17242276: Referred to as G4216T, G1406C, due to a different transcript used. Effects were similar to wildtype, and rescued abnormal phenotype (contraction rate and spatial patterns of Ca2+ release in ankyrin-B heterozygous and homozygous knockout mice. (B) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Uncertain:2 Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:17242276). -

Apr 21, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Gly1439Cys (c.4315G>T), was identified in exon 35 ANK2 (NM_001148.4) Given the weak case data and its prevalence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of Long QT syndrome (not including this patient's family). The case data is weak. This variant is present in ClinVar. It is interpreted as likely benign by GeneDx and Ambry genetics. It is interpreted as a variant of uncertain significance by Illumina Clinical Services. It has also been submitted by Royal Brompton, but they did not provide a classification. This variant was seen in 1 out of 855 unrelated patients referred for Long QT testing (Vieve et al 2013). The researchers classified it as a VUS/likely benign. Clinical information on this individual, including their QTc interval, is available for review. It is important to note that this patient is likely the same as a patient present in ClinVar, submitted by GeneDx. It was also present in 1 out of 403 individuals with Long QT syndrome (Mullally et al 2013). The glycine at codon 1439 is moderately conserved across species, as are neighboring amino acids. Nearby codons have been classified as likely benign or there are conflicting interpretations of pathogenicity. The variant was reported online in 71 of 122,869 individuals 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, Latino descent. Specifically, the variant was observed in 57 of 55,746 individuals of European descent (MAF=0.017%), 6 of 16,779 individuals of Latino descent, 4 of 11,150 individuals of Finnish descent, 2 of 7,651 individuals of African descent and 2 of 2,738 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

May 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with LQTS, HCM, and early onset atrial fibrillation; no case-specific clinical or segregation data were provided in these publications (PMID: 23174487, 25351510, 31638414); Identified in one individual of Mexican American ancestry from a control cohort of 190 anonymized individuals; variant reported as p.(G1406C) due to alternate nomenclature (PMID: 17242276); Functional studies in mouse neonatal cardiomyocytes suggest this variant may not impact ankyrin-B function; the clinical validity of these studies remains to be established (PMID: 17242276); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 25351510, 28988457, 22581653, 31638414, 17242276, 23174487) -

Long QT syndrome Uncertain:1 Benign:1

Jun 28, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy Uncertain:1

Mar 18, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.;D;T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	.;.;.;L;L;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.025	D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.035	D;D;D;D;D;D;D;T
Polyphen		0.035, 0.14, 0.017	.;B;.;B;.;.;B;.
Vest4		0.69, 0.63, 0.91, 0.93, 0.57, 0.41
MVP		0.86
MPC		1.4
ClinPred		0.17	T
GERP RS		6.1
Varity_R		0.71
gMVP		0.42

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: rs34591340; hg19: chr4-114267122; COSMIC: COSV99053407; COSMIC: COSV99053407;