rs7667099

Variant names:

• chr4-113189860-G-A
• rs7667099
• NM_001148.6:c.187-6508G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001148.6(ANK2):​c.187-6508G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,914 control chromosomes in the GnomAD database, including 7,448 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7448 hom., cov: 32)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.187-6508G>A		intron_variant	Intron 2 of 45	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.187-6508G>A		intron_variant	Intron 2 of 45	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46081 AN: 151796 Hom.: 7443 Cov.: 32

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 46094 AN: 151914 Hom.: 7448 Cov.: 32 AF XY: 0.299 AC XY: 22189 AN XY: 74250

African (AFR) AF: 0.405 AC: 16780 AN: 41384

American (AMR) AF: 0.263 AC: 4015 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1000 AN: 3472

East Asian (EAS) AF: 0.127 AC: 656 AN: 5168

South Asian (SAS) AF: 0.318 AC: 1527 AN: 4806

European-Finnish (FIN) AF: 0.220 AC: 2317 AN: 10544

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.279 AC: 18930 AN: 67958

Other (OTH) AF: 0.295 AC: 624 AN: 2112

Alfa AF: 0.291 Hom.: 1255

Bravo AF: 0.309

Asia WGS AF: 0.241 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.2
DANN	Benign	0.63
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7667099; hg19: chr4-114111016;