rs140926982
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001148.6(ANK2):āc.6648C>Gā(p.Gly2216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,054 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0021 ( 0 hom., cov: 32)
Exomes š: 0.0025 ( 8 hom. )
Consequence
ANK2
NM_001148.6 synonymous
NM_001148.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0120
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]
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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=-0.58).
BP6
?
Variant 4-113355266-C-G is Benign according to our data. Variant chr4-113355266-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 238585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113355266-C-G is described in Lovd as [Benign]. Variant chr4-113355266-C-G is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.012 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00207 (315/152250) while in subpopulation AMR AF= 0.00425 (65/15290). AF 95% confidence interval is 0.00342. There are 0 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 315 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.6648C>G | p.Gly2216= | synonymous_variant | 38/46 | ENST00000357077.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.6648C>G | p.Gly2216= | synonymous_variant | 38/46 | 1 | NM_001148.6 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00206 AC: 314AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00221 AC: 552AN: 250198Hom.: 4 AF XY: 0.00220 AC XY: 298AN XY: 135278
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GnomAD4 exome AF: 0.00247 AC: 3610AN: 1461804Hom.: 8 Cov.: 35 AF XY: 0.00249 AC XY: 1813AN XY: 727202
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GnomAD4 genome ? AF: 0.00207 AC: 315AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.00209 AC XY: 156AN XY: 74466
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2017 | Variant summary: The ANK2 c.6648C>G (p.Gly2216Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict loss/weakening effect on a cryptic splicing acceptor site. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 276/120418 control chromosomes (2 homozygotes) at a frequency of 0.002292, which is approximately 229 times the estimated maximal expected allele frequency of a pathogenic ANK2 variant (0.00001), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ANK2: BP4, BP7, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiac arrhythmia, ankyrin-B-related Benign:2
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. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Long QT syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2016 | 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
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at