rs121912705

chr4-113367764-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001148.6(ANK2):c.11231C>A(p.Thr3744Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3744P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:8 O:1
• Conservation: PhyloP100: 0.779

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 -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.17442057).
• BP6: Variant 4-113367764-C-A is Benign according to our data. Variant chr4-113367764-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18057.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=7, not_provided=1, Benign=1}. Variant chr4-113367764-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.11231C>A	p.Thr3744Asn	missense_variant	42/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.11231C>A	p.Thr3744Asn	missense_variant	42/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000625 AC: 157 AN: 251200 Hom.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135754

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 840 AN XY: 727232

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.000687 AC XY: 51 AN XY: 74282

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.000695

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ANK2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2017	- -

Cardiac arrhythmia, ankyrin-B-related Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. -

not specified Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 12, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2021	- -

Long QT syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

Cardiac arrhythmia Benign:1 Other:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2023

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	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	16
Dann	Benign	0.93
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	2.7e-10	A;A;A;A;A;A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.030	D;D;D;D;D;D;D
Sift4G	Benign	0.56	T;T;T;T;T;T;D
Polyphen		0.55	P;P;.;.;B;.;.
Vest4		0.20
MVP		0.65
MPC		0.21
ClinPred		0.019	T
GERP RS		3.0
Varity_R		0.052
gMVP		0.19

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: rs121912705; hg19: chr4-114288920;