dbSNP rs750625: ANK1:p.Val1755Val (chr8-41668396-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is The variant received -15 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_StrongBP7

The NM_000037.4(ANK1):c.5265G>A (p.Val1755Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.234 (AC=377,206) in the gnomAD database across 1,614,112 control chromosomes, including 45,182 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.272. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4040 hom., cov: 33)

Exomes 𝑓: 0.23 ( 41142 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.27

Publications

28 publications found

Variant links:

Genes affected

ANK1 (HGNC:492): (ankyrin 1) Ankyrins are a family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. 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. Ankyrin 1, the prototype of this family, was first discovered in the erythrocytes, but since has also been found in brain and muscles. Mutations in erythrocytic ankyrin 1 have been associated in approximately half of all patients with hereditary spherocytosis. Complex patterns of alternative splicing in the regulatory domain, giving rise to different isoforms of ankyrin 1 have been described. Truncated muscle-specific isoforms of ankyrin 1 resulting from usage of an alternate promoter have also been identified. [provided by RefSeq, Dec 2008]

ANK1 Gene-Disease associations (from GenCC):

hereditary spherocytosis
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
hereditary spherocytosis type 1
Inheritance: SD, AR, AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ANK1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000037.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -15 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2717 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000037.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK1	NM_000037.4	MANE Select	c.5265G>A	p.Val1755Val	synonymous	Exon 39 of 43	NP_000028.3
ANK1	NM_001142446.2		c.5388G>A	p.Val1796Val	synonymous	Exon 40 of 43	NP_001135918.1	P16157-21
ANK1	NM_020476.3		c.5265G>A	p.Val1755Val	synonymous	Exon 39 of 42	NP_065209.2	P16157-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK1	ENST00000289734.13	TSL:1 MANE Select	c.5265G>A	p.Val1755Val	synonymous	Exon 39 of 43	ENSP00000289734.8	P16157-3
ANK1	ENST00000265709.14	TSL:1	c.5388G>A	p.Val1796Val	synonymous	Exon 40 of 43	ENSP00000265709.8	P16157-21
ANK1	ENST00000347528.8	TSL:1	c.5265G>A	p.Val1755Val	synonymous	Exon 39 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34461

AN:

152128

Hom.:

4030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.376

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.201

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.249

GnomAD2 exomes

AF:

0.217

AC:

54591

AN:

251474

AF XY:

0.219

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.234

AC:

342714

AN:

1461866

Hom.:

41142

Cov.:

AF XY:

0.235

AC XY:

170673

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.202

AC:

6748

AN:

33480

American (AMR)

AF:

0.200

AC:

8932

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

7536

AN:

26136

East Asian (EAS)

AF:

0.131

AC:

5190

AN:

39700

South Asian (SAS)

AF:

0.200

AC:

17267

AN:

86258

European-Finnish (FIN)

AF:

0.206

AC:

11000

AN:

53416

Middle Eastern (MID)

AF:

0.283

AC:

1633

AN:

5768

European-Non Finnish (NFE)

AF:

0.243

AC:

270426

AN:

1111988

Other (OTH)

AF:

0.232

AC:

13982

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18067

36134

54201

72268

90335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9092

18184

27276

36368

45460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.227

AC:

34492

AN:

152246

Hom.:

4040

Cov.:

AF XY:

0.227

AC XY:

16879

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.199

AC:

8284

AN:

41546

American (AMR)

AF:

0.258

AC:

3951

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

1012

AN:

3468

East Asian (EAS)

AF:

0.127

AC:

660

AN:

5186

South Asian (SAS)

AF:

0.199

AC:

960

AN:

4818

European-Finnish (FIN)

AF:

0.201

AC:

2133

AN:

10606

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16543

AN:

68004

Other (OTH)

AF:

0.246

AC:

520

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1402

2804

4205

5607

7009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.231

AC:

61162

AN:

264690

Hom.:

7337

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.236

AC:

110733

AN:

468812

Hom.:

13817

Local populations

ABraOM SABE-WGS-1171

AF:

0.248

AC:

580

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.120

Denmark Genome

AF:

0.233

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.231

AC:

3007

AN:

13006

show subpopulations

European American

AF:

0.245

AC:

2107

AN:

8600

African American

AF:

0.204

AC:

900

AN:

4406

GenomeAsia100K

AF:

0.141

AC:

490

AN:

3478

show subpopulations

Oceania

AF:

0.0270

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.0997

AC:

AN:

702

Hom.:

South-East Asia

AF:

0.132

AC:

AN:

692

Hom.:

South Asia

AF:

0.148

AC:

215

AN:

1448

Hom.:

Africa

AF:

0.240

AC:

AN:

208

Hom.:

America

AF:

0.135

AC:

AN:

Hom.:

West Eurasia

AF:

0.232

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.115

AC:

830

AN:

7234

Qatari Genome

AF:

0.237

AC:

477

AN:

2010

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.139

AC:

17021

AN:

122770

Hom.:

1219

Turkish Variome

AF:

0.297

AC:

1999

AN:

6720

Hom.:

325

UK10K

AF:

0.247

AC:

1867

AN:

7562

show subpopulations

TwinsUK

AF:

0.245

AC:

874

AN:

3574

ALSPAC

AF:

0.250

AC:

964

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.133

AC:

1195

AN:

8960

Hom.:

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

2404 / 11002AF: 0.218506

3682 / 17524AF: 0.210112

BipEx

(Bipolar disorder (including schizoaffective))

6536 / 28420AF: 0.229979

6738 / 28844AF: 0.233601

Epi25

(Epilepsy)

9893 / 41958AF: 0.235783

15999 / 66888AF: 0.239191

SCHEMA

(Schizophrenia)

33954 / 137270AF: 0.247352

59660 / 225620AF: 0.264427

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spherocytosis type 1 (5)

not provided (3)

not specified (2)

Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.1

(source)

DANN

Benign

0.60

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

AlphaGenome AVI

Benign

9.0

(source)

GPN-Star LLR

-1.5

(source)

GPN-Star score

1.5

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.010

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over