4-113357121-C-T

Variant names:

• chr4-113357121-C-T
• rs3733617
• NM_001148.6:c.8503C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001148.6(ANK2):​c.8503C>T​(p.Pro2835Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,613,944 control chromosomes in the GnomAD database, including 7,897 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2835P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2963 hom., cov: 32)
  • Exomes 𝑓: 0.058 (4934 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.391
• Publications: 24 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 (MetaRNN=0.0031706393).
• BP6: Variant 4-113357121-C-T is Benign according to our data. Variant chr4-113357121-C-T is described in ClinVar as Benign. ClinVar VariationId is 191560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.8503C>T	p.Pro2835Ser	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.8644C>T	p.Pro2882Ser	missense	Exon 40 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.8620C>T	p.Pro2874Ser	missense	Exon 39 of 50	NP_001373104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.8503C>T	p.Pro2835Ser	missense	Exon 38 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.8644C>T	p.Pro2882Ser	missense	Exon 40 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.4427-3702C>T		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21187 AN: 152024 Hom.: 2951 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.0865 AC: 21704 AN: 250950 AF XY: 0.0810

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0805

GnomAD4 exome AF: 0.0580 AC: 84795 AN: 1461802 Hom.: 4934 Cov.: 35 AF XY: 0.0585 AC XY: 42522 AN XY: 727200

African (AFR) AF: 0.370 AC: 12387 AN: 33474

American (AMR) AF: 0.109 AC: 4886 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0858 AC: 2243 AN: 26132

East Asian (EAS) AF: 0.125 AC: 4967 AN: 39696

South Asian (SAS) AF: 0.112 AC: 9624 AN: 86252

European-Finnish (FIN) AF: 0.0210 AC: 1121 AN: 53420

Middle Eastern (MID) AF: 0.108 AC: 625 AN: 5768

European-Non Finnish (NFE) AF: 0.0397 AC: 44092 AN: 1111944

Other (OTH) AF: 0.0803 AC: 4850 AN: 60394

GnomAD4 genome AF: 0.140 AC: 21236 AN: 152142 Hom.: 2963 Cov.: 32 AF XY: 0.137 AC XY: 10224 AN XY: 74384

African (AFR) AF: 0.362 AC: 14998 AN: 41460

American (AMR) AF: 0.106 AC: 1622 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3470

East Asian (EAS) AF: 0.116 AC: 601 AN: 5174

South Asian (SAS) AF: 0.107 AC: 513 AN: 4816

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0398 AC: 2705 AN: 68006

Other (OTH) AF: 0.126 AC: 266 AN: 2114

Alfa AF: 0.0736 Hom.: 4329

Bravo AF: 0.156

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.342 AC: 1509

ESP6500EA AF: 0.0457 AC: 393

ExAC AF: 0.0900 AC: 10931

Asia WGS AF: 0.123 AC: 427 AN: 3478

EpiCase AF: 0.0443

EpiControl AF: 0.0421

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mar 18, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22100668)

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia, ankyrin-B-related Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.57
DANN	Benign	0.88
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.39
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.037
Sift	Benign	0.56	T
Sift4G	Benign	0.89	T
Vest4		0.046
MPC		0.080
ClinPred		0.00017	T
GERP RS		2.5
Varity_R		0.015
gMVP		0.043
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: rs3733617; hg19: chr4-114278277; COSMIC: COSV52146717; COSMIC: COSV52146717;