4-113369660-G-C

Variant names:

• chr4-113369660-G-C
• rs79577190
• NM_001148.6:c.11465G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001148.6(ANK2):​c.11465G>C​(p.Gly3822Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,614,074 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. G3822V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.542
• Publications: 14 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=0.0049439967).
• BP6: Variant 4-113369660-G-C is Benign according to our data. Variant chr4-113369660-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00204 (311/152222) while in subpopulation AFR AF = 0.00689 (286/41526). AF 95% confidence interval is 0.00623. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 311 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.11465G>C	p.Gly3822Ala	missense	Exon 43 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11606G>C	p.Gly3869Ala	missense	Exon 45 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.11582G>C	p.Gly3861Ala	missense	Exon 44 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.11465G>C	p.Gly3822Ala	missense	Exon 43 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.11606G>C	p.Gly3869Ala	missense	Exon 45 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.5210G>C	p.Gly1737Ala	missense	Exon 42 of 45	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00684

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000661 AC: 166 AN: 250966 AF XY: 0.000428

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000242 AC: 354 AN: 1461852 Hom.: 3 Cov.: 32 AF XY: 0.000219 AC XY: 159 AN XY: 727228

African (AFR) AF: 0.00806 AC: 270 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111994

Other (OTH) AF: 0.000497 AC: 30 AN: 60392

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74430

African (AFR) AF: 0.00689 AC: 286 AN: 41526

American (AMR) AF: 0.00137 AC: 21 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000124 Hom.: 1

Bravo AF: 0.00249

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.43
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.54
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.14
Sift	Benign	0.26	T
Sift4G	Benign	0.45	T
Polyphen		0.015	B
Vest4		0.094
MVP		0.52
MPC		0.15
ClinPred		0.0042	T
GERP RS		-4.0
Varity_R		0.027
gMVP		0.11
Mutation Taster		=94/6	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: rs79577190; hg19: chr4-114290816;