rs752213208

Variant names:

• chr4-113242195-G-A
• rs752213208
• NM_001148.6:c.877G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113242195-G-A
• chr4-113242195-G-C

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.877G>A​(p.Asp293Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,624 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).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 10.0
• Publications: 3 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=0.21715337).
• BP6: Variant 4-113242195-G-A is Benign according to our data. Variant chr4-113242195-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527005.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000102 (149/1461466) while in subpopulation SAS AF = 0.00029 (25/86240). AF 95% confidence interval is 0.000201. There are 1 homozygotes in GnomAdExome4. There are 82 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 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.877G>A	p.Asp293Asn	missense	Exon 9 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.928G>A	p.Asp310Asn	missense	Exon 9 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.904G>A	p.Asp302Asn	missense	Exon 8 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.877G>A	p.Asp293Asn	missense	Exon 9 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.928G>A	p.Asp310Asn	missense	Exon 9 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.877G>A	p.Asp293Asn	missense	Exon 9 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251426 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461466 Hom.: 1 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 727048

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86240

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000962 AC: 107 AN: 1111690

Other (OTH) AF: 0.000149 AC: 9 AN: 60386

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.70	N
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.32
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.49
MVP		0.82
MPC		1.5
ClinPred		0.29	T
GERP RS		4.6
Varity_R		0.67
gMVP		0.50
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs752213208; hg19: chr4-114163351;