rs35446871

Variant names:

• chr4-113381478-C-T
• rs35446871
• ENST00000506344.6:c.12390C>T

Variant summary

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

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.423

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=-0.89).
• 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 rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.*7C>T		3_prime_UTR_variant	Exon 46 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.*7C>T		3_prime_UTR_variant	Exon 46 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4519 AN: 152176 Hom.: 86 Cov.: 33

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

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.: 31 AF XY: 0.0306 AC XY: 22287 AN XY: 727186

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.: 86 Cov.: 33 AF XY: 0.0292 AC XY: 2178 AN XY: 74466

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.: 61

Bravo AF: 0.0304

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0347

EpiControl AF: 0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia, ankyrin-B-related Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Other links and lift over

dbSNP: rs35446871; hg19: chr4-114302634;