chr4-112904455-G-A

Variant names:

• chr4-112904455-G-A
• rs775400814
• ENST00000506722.5:c.-39G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386142.1(ANK2):​c.-39G>A variant causes a splice region change. The variant allele was found at a frequency of 0.00000235 in 1,277,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: ANK2 NM_001386142.1 splice_region
• Scores: Splicing: ADA: 0.8660
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.-39G>A		splice_region_variant	Exon 2 of 45		NP_001373071.1
ANK2	NM_001386143.1	c.-39G>A		splice_region_variant	Exon 2 of 48		NP_001373072.1
ANK2	NM_001354239.2	c.-39G>A		splice_region_variant	Exon 2 of 49		NP_001341168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.-39G>A		splice_region_variant	Exon 2 of 47	1		ENSP00000421067.1
ANK2	ENST00000506722.5	c.-39G>A		5_prime_UTR_variant	Exon 2 of 47	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-39G>A		splice_region_variant	Exon 2 of 48			ENSP00000499982.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000235 AC: 3 AN: 1277514 Hom.: 0 Cov.: 20 AF XY: 0.00000158 AC XY: 1 AN XY: 633554

African (AFR) AF: 0.00 AC: 0 AN: 27914

American (AMR) AF: 0.00 AC: 0 AN: 29332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23904

East Asian (EAS) AF: 0.00 AC: 0 AN: 33940

South Asian (SAS) AF: 0.00 AC: 0 AN: 68636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.00000304 AC: 3 AN: 985990

Other (OTH) AF: 0.00 AC: 0 AN: 53636

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.95
PhyloP100		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.71

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

Other links and lift over

dbSNP: rs775400814; hg19: chr4-113825611;