rs66785829

Positions:

• chr4-113365051-T-A
• chr4-113365051-T-C
• chr4-113365051-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001148.6(ANK2):​c.10901T>A​(p.Val3634Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,852 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts 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. V3634I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (22 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8 O:1
• Conservation: PhyloP100: 3.50

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.01469788).
• BP6: Variant 4-113365051-T-A is Benign according to our data. Variant chr4-113365051-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67599.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2, Benign=1, not_provided=1}. Variant chr4-113365051-T-A is described in Lovd as [Benign]. Variant chr4-113365051-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00206 (314/152274) while in subpopulation AMR AF= 0.00464 (71/15290). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.10901T>A	p.Val3634Asp	missense_variant	41/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.10901T>A	p.Val3634Asp	missense_variant	41/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00245 AC: 615 AN: 251264 Hom.: 4 AF XY: 0.00256 AC XY: 348 AN XY: 135796

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00209 AC: 3057 AN: 1461578 Hom.: 22 Cov.: 32 AF XY: 0.00221 AC XY: 1610 AN XY: 727094

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74468

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00266 Hom.: 1

Bravo AF: 0.00196

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	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: 31920912, 32164423, 24025405, 17242276, 27884173, 23631430, 23174487) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANK2: PM5, BP4, BS2 -

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:17242276). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 18, 2019

- -

Cardiac arrhythmia, ankyrin-B-related Uncertain:1

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ANK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial dilated cardiomyopathy and peripheral neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 03, 2019

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

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	0.61
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.97
Eigen	Benign	-0.14
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N;N;N;N;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.36	T;T;T;D;T;T;D
Sift4G	Benign	0.28	T;T;D;D;T;T;T
Polyphen		0.039	B;B;.;.;B;.;.
Vest4		0.69
MVP		0.98
MPC		0.16
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.72

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: rs66785829; hg19: chr4-114286207;