rs371787039

chr4-113288458-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001148.6(ANK2):c.2249A>G(p.Gln750Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.21

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.014538527).
• BP6: Variant 4-113288458-A-G is Benign according to our data. Variant chr4-113288458-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 377473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113288458-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.2249A>G	p.Gln750Arg	missense_variant	20/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.2249A>G	p.Gln750Arg	missense_variant	20/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251396 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135880

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.0000908 AC XY: 66 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74488

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.00751 AC: 26 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2021	This variant is associated with the following publications: (PMID: 32145446) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ANK2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiac arrhythmia, ankyrin-B-related Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 01, 2021	- -

ANK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 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). -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

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	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.069
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.76	N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.052	T;D;D;D;D;D;D;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T
Polyphen		0.32, 0.56, 0.54	.;.;B;.;P;P;.;.
Vest4		0.26, 0.27, 0.29, 0.35
MVP		0.70
MPC		1.0
ClinPred		0.028	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.25

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: rs371787039; hg19: chr4-114209614;