4-113336045-C-T

Variant names:

• chr4-113336045-C-T
• rs3736575
• NM_001148.6:c.3579C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001148.6(ANK2):​c.3579C>T​(p.Arg1193Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,414 control chromosomes in the GnomAD database, including 20,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6971 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13541 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.97
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.163).
• BP6: Variant 4-113336045-C-T is Benign according to our data. Variant chr4-113336045-C-T is described in ClinVar as Benign. ClinVar VariationId is 136390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.54 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.3579C>T	p.Arg1193Arg	synonymous	Exon 30 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.3720C>T	p.Arg1240Arg	synonymous	Exon 32 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.3696C>T	p.Arg1232Arg	synonymous	Exon 31 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.3579C>T	p.Arg1193Arg	synonymous	Exon 30 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.3720C>T	p.Arg1240Arg	synonymous	Exon 32 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.3579C>T	p.Arg1193Arg	synonymous	Exon 30 of 45	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34420 AN: 151914 Hom.: 6943 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0621

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.137 AC: 34303 AN: 249536 AF XY: 0.129

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0990

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0616

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.113 AC: 165864 AN: 1461382 Hom.: 13541 Cov.: 32 AF XY: 0.113 AC XY: 82132 AN XY: 726986

African (AFR) AF: 0.567 AC: 18978 AN: 33460

American (AMR) AF: 0.142 AC: 6350 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2654 AN: 26130

East Asian (EAS) AF: 0.125 AC: 4959 AN: 39692

South Asian (SAS) AF: 0.130 AC: 11241 AN: 86242

European-Finnish (FIN) AF: 0.0658 AC: 3510 AN: 53328

Middle Eastern (MID) AF: 0.178 AC: 1008 AN: 5658

European-Non Finnish (NFE) AF: 0.0980 AC: 108994 AN: 1111794

Other (OTH) AF: 0.135 AC: 8170 AN: 60364

GnomAD4 genome AF: 0.227 AC: 34501 AN: 152032 Hom.: 6971 Cov.: 32 AF XY: 0.222 AC XY: 16486 AN XY: 74306

African (AFR) AF: 0.546 AC: 22593 AN: 41414

American (AMR) AF: 0.157 AC: 2398 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3472

East Asian (EAS) AF: 0.117 AC: 601 AN: 5156

South Asian (SAS) AF: 0.122 AC: 590 AN: 4818

European-Finnish (FIN) AF: 0.0621 AC: 656 AN: 10570

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6841 AN: 67998

Other (OTH) AF: 0.196 AC: 413 AN: 2110

Alfa AF: 0.145 Hom.: 4343

Bravo AF: 0.249

Asia WGS AF: 0.149 AC: 517 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0988

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.65
DANN	Benign	0.83
PhyloP100		-4.0
Mutation Taster		=89/11	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: rs3736575; hg19: chr4-114257201; COSMIC: COSV52190796; COSMIC: COSV52190796;