rs121912705

Variant names:

• chr4-113367764-C-A
• rs121912705
• NM_001148.6:c.11231C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113367764-C-A
• chr4-113367764-C-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001148.6(ANK2):​c.11231C>A​(p.Thr3744Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T3744P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:8 O:2
• Conservation: PhyloP100: 0.779
• Publications: 18 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17442057).
• BP6: Variant 4-113367764-C-A is Benign according to our data. Variant chr4-113367764-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18057.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000736 (112/152112) while in subpopulation NFE AF = 0.00137 (93/68036). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 112 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.11231C>A	p.Thr3744Asn	missense	Exon 42 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11372C>A	p.Thr3791Asn	missense	Exon 44 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.11348C>A	p.Thr3783Asn	missense	Exon 43 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.11231C>A	p.Thr3744Asn	missense	Exon 42 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.11372C>A	p.Thr3791Asn	missense	Exon 44 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4976C>A	p.Thr1659Asn	missense	Exon 41 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000625 AC: 157 AN: 251200 AF XY: 0.000626

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 840 AN XY: 727232

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00156 AC: 1737 AN: 1111980

Other (OTH) AF: 0.000397 AC: 24 AN: 60394

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.000687 AC XY: 51 AN XY: 74282

African (AFR) AF: 0.000362 AC: 15 AN: 41408

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.000695

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
1	2	-	Cardiac arrhythmia, ankyrin-B-related (4)
-	1	1	Long QT syndrome (2)
-	1	1	not specified (2)
-	-	1	Cardiac arrhythmia (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.78
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.16
Sift	Benign	0.030	D
Sift4G	Benign	0.56	T
Polyphen		0.55	P
Vest4		0.20
MVP		0.65
MPC		0.21
ClinPred		0.019	T
GERP RS		3.0
Varity_R		0.052
gMVP		0.19
Mutation Taster		=13/87	disease causing

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: rs121912705; hg19: chr4-114288920;