rs142159132

Variant names:

• chr4-113264911-A-G
• rs142159132
• NM_001148.6:c.1401A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001148.6(ANK2):​c.1401A>G​(p.Ala467Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,565,198 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.04
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-113264911-A-G is Benign according to our data. Variant chr4-113264911-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00265 (404/152310) while in subpopulation NFE AF = 0.00418 (284/68016). AF 95% confidence interval is 0.00378. There are 0 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 404 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001148.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.1401A>G	p.Ala467Ala	synonymous	Exon 14 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.1452A>G	p.Ala484Ala	synonymous	Exon 14 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.1428A>G	p.Ala476Ala	synonymous	Exon 13 of 50	NP_001373104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.1401A>G	p.Ala467Ala	synonymous	Exon 14 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.1452A>G	p.Ala484Ala	synonymous	Exon 14 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.1401A>G	p.Ala467Ala	synonymous	Exon 14 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00245 AC: 433 AN: 176464 AF XY: 0.00228

Gnomad AFR exome AF: 0.000467

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00803

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000247

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00334 AC: 4721 AN: 1412888 Hom.: 8 Cov.: 31 AF XY: 0.00333 AC XY: 2323 AN XY: 697980

African (AFR) AF: 0.000707 AC: 23 AN: 32544

American (AMR) AF: 0.00257 AC: 96 AN: 37406

Ashkenazi Jewish (ASJ) AF: 0.00888 AC: 224 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 37346

South Asian (SAS) AF: 0.000450 AC: 36 AN: 80076

European-Finnish (FIN) AF: 0.000219 AC: 11 AN: 50244

Middle Eastern (MID) AF: 0.0133 AC: 76 AN: 5710

European-Non Finnish (NFE) AF: 0.00374 AC: 4066 AN: 1085764

Other (OTH) AF: 0.00323 AC: 189 AN: 58560

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74480

African (AFR) AF: 0.000553 AC: 23 AN: 41578

American (AMR) AF: 0.00248 AC: 38 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

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

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00418 AC: 284 AN: 68016

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Cardiac arrhythmia, ankyrin-B-related (4)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.48
PhyloP100		-3.0
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142159132; hg19: chr4-114186067; COSMIC: COSV52192220;