rs142908806

chr4-113358989-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001148.6(ANK2):c.10371G>A(p.Thr3457=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,034 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (21 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0570

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-113358989-G-A is Benign according to our data. Variant chr4-113358989-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113358989-G-A is described in Lovd as [Benign]. Variant chr4-113358989-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.057 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00209 (318/152304) while in subpopulation AMR AF= 0.00471 (72/15294). AF 95% confidence interval is 0.00383. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.10371G>A	p.Thr3457=	synonymous_variant	38/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.10371G>A	p.Thr3457=	synonymous_variant	38/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00250 AC: 624 AN: 249740 Hom.: 4 AF XY: 0.00262 AC XY: 355 AN XY: 135394

Gnomad AFR exome AF: 0.000513

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00211 AC: 3086 AN: 1461730 Hom.: 21 Cov.: 34 AF XY: 0.00223 AC XY: 1622 AN XY: 727168

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00360 Hom.: 4

Bravo AF: 0.00199

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

ANK2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

ANK2: BP4, BP7, BS2 -

Long QT syndrome Benign:1

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

Jul 21, 2015

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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.52
Dann	Benign	0.74

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: rs142908806; hg19: chr4-114280145;