chr4-112904538-A-G

Variant names:

• chr4-112904538-A-G
• rs76764953
• ENST00000506722.5:c.21+24A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000683180.1(ANK2):​n.227A>G 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 0.00146 in 1,444,442 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (9 hom.)
• Consequence: ANK2 ENST00000683180.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-112904538-A-G is Benign according to our data. Variant chr4-112904538-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1195276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00743 (1131/152310) while in subpopulation AFR AF = 0.0252 (1048/41580). AF 95% confidence interval is 0.0239. There are 8 homozygotes in GnomAd4. There are 549 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1131 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.21+24A>G		intron_variant	Intron 2 of 44		NP_001373071.1
ANK2	NM_001386143.1	c.21+24A>G		intron_variant	Intron 2 of 47		NP_001373072.1
ANK2	NM_001386186.2	c.72+198321A>G		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+24A>G		intron_variant	Intron 2 of 46	1		ENSP00000421067.1
ANK2	ENST00000683180.1	n.227A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ANK2	ENST00000672209.1	c.21+24A>G		intron_variant	Intron 2 of 47			ENSP00000499982.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1125 AN: 152192 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00182 AC: 233 AN: 127938 AF XY: 0.00147

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000755 AC: 976 AN: 1292132 Hom.: 9 Cov.: 22 AF XY: 0.000652 AC XY: 417 AN XY: 639976

African (AFR) AF: 0.0247 AC: 692 AN: 27986

American (AMR) AF: 0.00195 AC: 54 AN: 27732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23962

East Asian (EAS) AF: 0.00 AC: 0 AN: 34154

South Asian (SAS) AF: 0.0000866 AC: 6 AN: 69254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48834

Middle Eastern (MID) AF: 0.00201 AC: 11 AN: 5470

European-Non Finnish (NFE) AF: 0.000123 AC: 123 AN: 1000546

Other (OTH) AF: 0.00166 AC: 90 AN: 54194

GnomAD4 genome AF: 0.00743 AC: 1131 AN: 152310 Hom.: 8 Cov.: 32 AF XY: 0.00737 AC XY: 549 AN XY: 74482

African (AFR) AF: 0.0252 AC: 1048 AN: 41580

American (AMR) AF: 0.00353 AC: 54 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67998

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00402 Hom.: 2

Bravo AF: 0.00866

Asia WGS AF: 0.00175 AC: 6 AN: 3436

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 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	-0.55
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		1.2
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: rs76764953; hg19: chr4-113825694;