rs28377576

Variant names:

• chr4-113355724-T-C
• rs28377576
• NM_001148.6:c.7106T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-113355724-T-C
• chr4-113355724-T-G

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.7106T>C​(p.Val2369Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,532 control chromosomes in the GnomAD database, including 10,120 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2369G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1310 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8810 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0710
• Publications: 26 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=0.0010992885).
• BP6: Variant 4-113355724-T-C is Benign according to our data. Variant chr4-113355724-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 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.7106T>C	p.Val2369Ala	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.7247T>C	p.Val2416Ala	missense	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.7223T>C	p.Val2408Ala	missense	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.7106T>C	p.Val2369Ala	missense	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.7247T>C	p.Val2416Ala	missense	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4427-5099T>C		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18656 AN: 151688 Hom.: 1308 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.0945 AC: 23702 AN: 250714 AF XY: 0.0935

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0635

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.105 AC: 154195 AN: 1461726 Hom.: 8810 Cov.: 35 AF XY: 0.104 AC XY: 75891 AN XY: 727166

African (AFR) AF: 0.185 AC: 6195 AN: 33468

American (AMR) AF: 0.0670 AC: 2994 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3118 AN: 26124

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39690

South Asian (SAS) AF: 0.0365 AC: 3150 AN: 86256

European-Finnish (FIN) AF: 0.107 AC: 5715 AN: 53406

Middle Eastern (MID) AF: 0.164 AC: 948 AN: 5764

European-Non Finnish (NFE) AF: 0.113 AC: 125528 AN: 1111916

Other (OTH) AF: 0.108 AC: 6535 AN: 60388

GnomAD4 genome AF: 0.123 AC: 18677 AN: 151806 Hom.: 1310 Cov.: 32 AF XY: 0.120 AC XY: 8882 AN XY: 74216

African (AFR) AF: 0.175 AC: 7238 AN: 41402

American (AMR) AF: 0.0937 AC: 1428 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3466

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5156

South Asian (SAS) AF: 0.0278 AC: 133 AN: 4784

European-Finnish (FIN) AF: 0.100 AC: 1059 AN: 10556

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8049 AN: 67884

Other (OTH) AF: 0.130 AC: 273 AN: 2108

Alfa AF: 0.117 Hom.: 3443

Bravo AF: 0.127

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.106 AC: 409

ESP6500AA AF: 0.186 AC: 819

ESP6500EA AF: 0.116 AC: 1000

ExAC AF: 0.0981 AC: 11905

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.128

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.59
DANN	Benign	0.50
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.071
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.055
Sift	Benign	0.57	T
Sift4G	Benign	0.78	T
Vest4		0.036
MPC		0.094
ClinPred		0.0012	T
GERP RS		0.026
Varity_R		0.019
gMVP		0.026
Mutation Taster		=96/4	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: rs28377576; hg19: chr4-114276880; COSMIC: COSV52178253; COSMIC: COSV52178253;