rs142078935

Variant names:

• chr4-113356015-G-A
• rs142078935
• NM_001148.6:c.7397G>A

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.7397G>A​(p.Arg2466His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 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. R2466C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (3 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.31
• Publications: 5 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=0.009256244).
• BP6: Variant 4-113356015-G-A is Benign according to our data. Variant chr4-113356015-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 180272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000755 (115/152252) while in subpopulation NFE AF = 0.000912 (62/68014). AF 95% confidence interval is 0.000729. There are 1 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 115 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.7397G>A	p.Arg2466His	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.7538G>A	p.Arg2513His	missense	Exon 40 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.7514G>A	p.Arg2505His	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.7397G>A	p.Arg2466His	missense	Exon 38 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.7538G>A	p.Arg2513His	missense	Exon 40 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.4427-4808G>A		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000714 AC: 179 AN: 250650 AF XY: 0.000657

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.000778

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000516 AC: 755 AN: 1461822 Hom.: 3 Cov.: 35 AF XY: 0.000517 AC XY: 376 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00361 AC: 193 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000471 AC: 524 AN: 1111958

Other (OTH) AF: 0.000464 AC: 28 AN: 60394

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74440

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000672 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiac arrhythmia, ankyrin-B-related (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.060
Sift	Benign	0.16	T
Sift4G	Benign	0.59	T
Vest4		0.072
MVP		0.41
MPC		0.099
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.040
gMVP		0.079
Mutation Taster		=93/7	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: rs142078935; hg19: chr4-114277171;