rs145895389

Variant names:

• chr4-113356972-C-T
• rs145895389
• NM_001148.6:c.8354C>T

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.8354C>T​(p.Ser2785Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (8 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.589
• Publications: 7 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=0.0053032637).
• BP6: Variant 4-113356972-C-T is Benign according to our data. Variant chr4-113356972-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191540.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 = 0.00163 (248/152278) while in subpopulation NFE AF = 0.00309 (210/68006). AF 95% confidence interval is 0.00275. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 248 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.8354C>T	p.Ser2785Leu	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.8495C>T	p.Ser2832Leu	missense	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.8471C>T	p.Ser2824Leu	missense	Exon 39 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.8354C>T	p.Ser2785Leu	missense	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.8495C>T	p.Ser2832Leu	missense	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4427-3851C>T		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00161 AC: 402 AN: 250120 AF XY: 0.00161

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00234 AC: 3416 AN: 1461686 Hom.: 8 Cov.: 35 AF XY: 0.00228 AC XY: 1659 AN XY: 727152

African (AFR) AF: 0.000359 AC: 12 AN: 33472

American (AMR) AF: 0.000492 AC: 22 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00107 AC: 57 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00280 AC: 3115 AN: 1111866

Other (OTH) AF: 0.00257 AC: 155 AN: 60384

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74456

African (AFR) AF: 0.000409 AC: 17 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 68006

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

Alfa AF: 0.00229 Hom.: 2

Bravo AF: 0.00143

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Cardiac arrhythmia, ankyrin-B-related (3)
-	-	3	not provided (3)
-	-	1	ANK2-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.8
DANN	Benign	0.064
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.59
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.051
Sift	Benign	0.25	T
Sift4G	Benign	0.12	T
Vest4		0.055
MVP		0.40
MPC		0.071
ClinPred		0.0043	T
GERP RS		3.7
Varity_R		0.076
gMVP		0.018
Mutation Taster		=99/1	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: rs145895389; hg19: chr4-114278128;