chr4-113381478-C-T

Position:

chr4-113381478-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001386174.1(ANK2):c.12390C>T(p.Ile4130Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,614,054 control chromosomes in the GnomAD database, including 877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 86 hom., cov: 33)

Exomes 𝑓: 0.031 ( 791 hom. )

Consequence

ANK2
NM_001386174.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.423

Variant links:

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]

ANK2 links:

ANK2 (HGNC:):

ANK2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 4-113381478-C-T is Benign according to our data. Variant chr4-113381478-C-T is described in ClinVar as [Benign]. Clinvar id is 136400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113381478-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.423 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0297 (4522/152294) while in subpopulation NFE AF= 0.033 (2243/68028). AF 95% confidence interval is 0.0318. There are 86 homozygotes in gnomad4. There are 2178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.*7C>T		3_prime_UTR_variant	46/46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.*7C>T		3_prime_UTR_variant	46/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4519

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0330

Gnomad OTH

AF:

0.0382

GnomAD3 exomes

AF:

0.0280

AC:

7035

AN:

251000

Hom.:

129

AF XY:

0.0274

AC XY:

3721

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00595

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.0370

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0311

AC:

45401

AN:

1461760

Hom.:

791

Cov.:

AF XY:

0.0306

AC XY:

22287

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0284

Gnomad4 AMR exome

AF:

0.0226

Gnomad4 ASJ exome

AF:

0.0507

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00641

Gnomad4 FIN exome

AF:

0.0361

Gnomad4 NFE exome

AF:

0.0338

Gnomad4 OTH exome

AF:

0.0305

GnomAD4 genome

AF:

0.0297

AC:

4522

AN:

152294

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2178

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0275

Gnomad4 AMR

AF:

0.0282

Gnomad4 ASJ

AF:

0.0568

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0330

Gnomad4 NFE

AF:

0.0330

Gnomad4 OTH

AF:

0.0378

Alfa

AF:

0.0330

Hom.:

Bravo

AF:

0.0304

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0347

EpiControl

AF:

0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	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	-	- -

Cardiac arrhythmia, ankyrin-B-related

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.7

DANN

Benign

0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over