4-112861770-T-C

Variant names:

• chr4-112861770-T-C
• rs895763
• ENST00000506722.5:c.-39-42685T>C

Variant summary

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

The ENST00000506722.5(ANK2):​c.-39-42685T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 151,644 control chromosomes in the GnomAD database, including 22,709 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 0.53 (22709 hom., cov: 30)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.780
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.-39-42685T>C		intron_variant	Intron 1 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.-39-42685T>C		intron_variant	Intron 1 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+155553T>C		intron_variant	Intron 1 of 46		NP_001373115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.-39-42685T>C		intron_variant	Intron 1 of 46	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-39-42685T>C		intron_variant	Intron 1 of 47			ENSP00000499982.1
ANK2	ENST00000673298.1	c.-39-42685T>C		intron_variant	Intron 1 of 46			ENSP00000500245.1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 80885 AN: 151526 Hom.: 22647 Cov.: 30

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.534 AC: 81011 AN: 151644 Hom.: 22709 Cov.: 30 AF XY: 0.539 AC XY: 39965 AN XY: 74092

African (AFR) AF: 0.668 AC: 27588 AN: 41292

American (AMR) AF: 0.578 AC: 8804 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1231 AN: 3468

East Asian (EAS) AF: 0.807 AC: 4173 AN: 5168

South Asian (SAS) AF: 0.510 AC: 2456 AN: 4816

European-Finnish (FIN) AF: 0.504 AC: 5261 AN: 10448

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.440 AC: 29886 AN: 67904

Other (OTH) AF: 0.512 AC: 1082 AN: 2112

Alfa AF: 0.457 Hom.: 25378

Bravo AF: 0.551

Asia WGS AF: 0.690 AC: 2395 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.73
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs895763; hg19: chr4-113782926;