4-112904566-G-A

Variant names:

• chr4-112904566-G-A
• rs1448222
• ENST00000506722.5:c.21+52G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000683180.1(ANK2):​n.255G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,332,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ANK2 ENST00000683180.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.828
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-112904566-G-A is Benign according to our data. Variant chr4-112904566-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1200065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00293 (446/152148) while in subpopulation AFR AF = 0.0104 (430/41534). AF 95% confidence interval is 0.00955. There are 1 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 446 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.21+52G>A		intron_variant	Intron 2 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.21+52G>A		intron_variant	Intron 2 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+198349G>A		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.21+52G>A		intron_variant	Intron 2 of 46	1		ENSP00000421067.1
ANK2	ENST00000683180.1	n.255G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ANK2	ENST00000672209.1	c.21+52G>A		intron_variant	Intron 2 of 47			ENSP00000499982.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152030 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000315 AC: 372 AN: 1180296 Hom.: 0 AF XY: 0.000282 AC XY: 166 AN XY: 588866

African (AFR) AF: 0.0107 AC: 268 AN: 25132

American (AMR) AF: 0.00104 AC: 26 AN: 24954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22894

East Asian (EAS) AF: 0.00 AC: 0 AN: 32852

South Asian (SAS) AF: 0.0000309 AC: 2 AN: 64764

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48430

Middle Eastern (MID) AF: 0.000381 AC: 2 AN: 5254

European-Non Finnish (NFE) AF: 0.0000486 AC: 44 AN: 905728

Other (OTH) AF: 0.000577 AC: 29 AN: 50288

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152148 Hom.: 1 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74398

African (AFR) AF: 0.0104 AC: 430 AN: 41534

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67960

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00334

Asia WGS AF: 0.000292 AC: 1 AN: 3438

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.19
DANN	Benign	0.55
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1448222; hg19: chr4-113825722;