chr4-113365051-T-A

Variant names:

• chr4-113365051-T-A
• rs66785829
• NM_001148.6:c.10901T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001148.6(ANK2):​c.10901T>A​(p.Val3634Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,852 control chromosomes in the GnomAD database, including 23 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. V3634A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (22 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 3.50
• Publications: 30 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01469788).
• BP6: Variant 4-113365051-T-A is Benign according to our data. Variant chr4-113365051-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67599.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00206 (314/152274) while in subpopulation AMR AF = 0.00464 (71/15290). AF 95% confidence interval is 0.00378. 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 314 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.10901T>A	p.Val3634Asp	missense	Exon 41 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11042T>A	p.Val3681Asp	missense	Exon 43 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.11018T>A	p.Val3673Asp	missense	Exon 42 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.10901T>A	p.Val3634Asp	missense	Exon 41 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.11042T>A	p.Val3681Asp	missense	Exon 43 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4646T>A	p.Val1549Asp	missense	Exon 40 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00245 AC: 615 AN: 251264 AF XY: 0.00256

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00209 AC: 3057 AN: 1461578 Hom.: 22 Cov.: 32 AF XY: 0.00221 AC XY: 1610 AN XY: 727094

African (AFR) AF: 0.000807 AC: 27 AN: 33458

American (AMR) AF: 0.00165 AC: 74 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86258

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53388

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5764

European-Non Finnish (NFE) AF: 0.00215 AC: 2393 AN: 1111798

Other (OTH) AF: 0.00306 AC: 185 AN: 60372

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74468

African (AFR) AF: 0.000313 AC: 13 AN: 41554

American (AMR) AF: 0.00464 AC: 71 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68014

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00266 Hom.: 1

Bravo AF: 0.00196

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ANK2-related disorder (1)
-	-	1	Cardiac arrhythmia (2)
-	1	-	Cardiac arrhythmia, ankyrin-B-related (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial dilated cardiomyopathy and peripheral neuropathy (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.61
Sift	Benign	0.36	T
Sift4G	Benign	0.28	T
Polyphen		0.039	B
Vest4		0.69
MVP		0.98
MPC		0.16
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.72
Mutation Taster		=77/23	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: rs66785829; hg19: chr4-114286207;