4-113373306-C-T

Variant names:

• chr4-113373306-C-T
• rs121912706
• NM_001148.6:c.11716C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001148.6(ANK2):​c.11716C>T​(p.Arg3906Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3906Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:9 O:1
• Conservation: PhyloP100: 2.19
• Publications: 35 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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate, PrimateAI was below the threshold]
• BP6: Variant 4-113373306-C-T is Benign according to our data. Variant chr4-113373306-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18059.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000933 (142/152196) while in subpopulation NFE AF = 0.00162 (110/68000). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 142 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.11716C>T	p.Arg3906Trp	missense	Exon 45 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11950C>T	p.Arg3984Trp	missense	Exon 48 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.11926C>T	p.Arg3976Trp	missense	Exon 47 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.11716C>T	p.Arg3906Trp	missense	Exon 45 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.11950C>T	p.Arg3984Trp	missense	Exon 48 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.5461C>T	p.Arg1821Trp	missense	Exon 44 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00102 AC: 255 AN: 251088 AF XY: 0.000951

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00128 AC: 1876 AN: 1461796 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 889 AN XY: 727204

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00154 AC: 1713 AN: 1111938

Other (OTH) AF: 0.00128 AC: 77 AN: 60390

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74416

African (AFR) AF: 0.000313 AC: 13 AN: 41530

American (AMR) AF: 0.000654 AC: 10 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00112 AC: 136

EpiCase AF: 0.00153

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiac arrhythmia, ankyrin-B-related (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	ANK2-related disorder (1)
-	-	1	Cardiac arrhythmia (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
1	-	-	Death in infancy (1)
-	-	1	Long QT syndrome (1)
1	-	-	Long QT syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.36	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.2
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.88
MPC		0.45
ClinPred		0.15	T
GERP RS		5.2
PromoterAI		-0.0088	Neutral
Varity_R		0.33
gMVP		0.44
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912706; hg19: chr4-114294462; COSMIC: COSV52148627; COSMIC: COSV52148627;