rs3733615

Variant names:

• chr4-113355728-A-G
• rs3733615
• NM_001148.6:c.7110A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001148.6(ANK2):​c.7110A>G​(p.Gln2370Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,848 control chromosomes in the GnomAD database, including 31,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (8094 hom., cov: 32)
  • Exomes 𝑓: 0.16 (23364 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.58
• Publications: 19 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=-0.84).
• BP6: Variant 4-113355728-A-G is Benign according to our data. Variant chr4-113355728-A-G is described in ClinVar as Benign. ClinVar VariationId is 257582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

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.7110A>G	p.Gln2370Gln	synonymous	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.7251A>G	p.Gln2417Gln	synonymous	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.7227A>G	p.Gln2409Gln	synonymous	Exon 39 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.7110A>G	p.Gln2370Gln	synonymous	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.7251A>G	p.Gln2417Gln	synonymous	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4427-5095A>G		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40829 AN: 152008 Hom.: 8068 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.183 AC: 45806 AN: 250646 AF XY: 0.176

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.164 AC: 239990 AN: 1461722 Hom.: 23364 Cov.: 35 AF XY: 0.163 AC XY: 118852 AN XY: 727164

African (AFR) AF: 0.580 AC: 19413 AN: 33470

American (AMR) AF: 0.177 AC: 7924 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5361 AN: 26126

East Asian (EAS) AF: 0.125 AC: 4979 AN: 39688

South Asian (SAS) AF: 0.148 AC: 12794 AN: 86254

European-Finnish (FIN) AF: 0.128 AC: 6835 AN: 53408

Middle Eastern (MID) AF: 0.274 AC: 1582 AN: 5766

European-Non Finnish (NFE) AF: 0.153 AC: 169620 AN: 1111910

Other (OTH) AF: 0.190 AC: 11482 AN: 60386

GnomAD4 genome AF: 0.269 AC: 40903 AN: 152126 Hom.: 8094 Cov.: 32 AF XY: 0.263 AC XY: 19565 AN XY: 74400

African (AFR) AF: 0.559 AC: 23173 AN: 41440

American (AMR) AF: 0.202 AC: 3082 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3470

East Asian (EAS) AF: 0.117 AC: 606 AN: 5186

South Asian (SAS) AF: 0.135 AC: 650 AN: 4830

European-Finnish (FIN) AF: 0.121 AC: 1279 AN: 10610

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10758 AN: 67984

Other (OTH) AF: 0.262 AC: 553 AN: 2114

Alfa AF: 0.234 Hom.: 2894

Bravo AF: 0.290

Asia WGS AF: 0.155 AC: 538 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.170

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cardiac arrhythmia, ankyrin-B-related (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.50
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs3733615; hg19: chr4-114276884; COSMIC: COSV52165700; COSMIC: COSV52165700;