ENST00000506722.5:c.-40+9357C>T

Variant names:

• chr4-112827621-C-T
• rs13108692
• ENST00000506722.5:c.-40+9357C>T

Variant summary

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

The ENST00000506722.5(ANK2):​c.-40+9357C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 845,392 control chromosomes in the GnomAD database, including 37,248 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 (6917 hom., cov: 32)
  • Exomes 𝑓: 0.29 (30331 hom.)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.378
• 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

LOC100422627 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100422627		n.112827621C>T		intragenic_variant
ANK2	NM_001386142.1	c.-40+9357C>T		intron_variant	Intron 1 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.-40+9357C>T		intron_variant	Intron 1 of 47		NP_001373072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.-40+9357C>T		intron_variant	Intron 1 of 46	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-40+9357C>T		intron_variant	Intron 1 of 47			ENSP00000499982.1
ANK2	ENST00000673298.1	c.-40+9357C>T		intron_variant	Intron 1 of 46			ENSP00000500245.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45406 AN: 151940 Hom.: 6900 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.328

GnomAD4 exome AF: 0.292 AC: 202274 AN: 693334 Hom.: 30331 Cov.: 9 AF XY: 0.294 AC XY: 108480 AN XY: 368670

African (AFR) AF: 0.270 AC: 4816 AN: 17816

American (AMR) AF: 0.336 AC: 11405 AN: 33936

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 5513 AN: 17906

East Asian (EAS) AF: 0.332 AC: 11956 AN: 35978

South Asian (SAS) AF: 0.325 AC: 19876 AN: 61170

European-Finnish (FIN) AF: 0.338 AC: 16408 AN: 48582

Middle Eastern (MID) AF: 0.336 AC: 1367 AN: 4070

European-Non Finnish (NFE) AF: 0.274 AC: 120325 AN: 439812

Other (OTH) AF: 0.311 AC: 10608 AN: 34064

GnomAD4 genome AF: 0.299 AC: 45462 AN: 152058 Hom.: 6917 Cov.: 32 AF XY: 0.301 AC XY: 22377 AN XY: 74318

African (AFR) AF: 0.274 AC: 11354 AN: 41490

American (AMR) AF: 0.332 AC: 5069 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3468

East Asian (EAS) AF: 0.348 AC: 1798 AN: 5172

South Asian (SAS) AF: 0.328 AC: 1580 AN: 4822

European-Finnish (FIN) AF: 0.338 AC: 3570 AN: 10558

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20030 AN: 67960

Other (OTH) AF: 0.333 AC: 703 AN: 2112

Alfa AF: 0.290 Hom.: 1080

Bravo AF: 0.300

Asia WGS AF: 0.389 AC: 1351 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	6.1
DANN	Benign	0.49
PhyloP100		0.38
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: rs13108692; hg19: chr4-113748777; COSMIC: COSV69887966; COSMIC: COSV69887966;