dbSNP rs61758865: ANK1:p.Ala530Ala (chr8-41715664-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000037.4(ANK1):c.1590C>T(p.Ala530Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,460 control chromosomes in the GnomAD database, including 151 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 0.0064 ( 5 hom., cov: 33)

Exomes 𝑓: 0.011 ( 146 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.104

Publications

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

ANK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 8-41715664-G-A is Benign according to our data. Variant chr8-41715664-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261292.

BP7

Synonymous conserved (PhyloP=-0.104 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00643 (980/152334) while in subpopulation NFE AF = 0.0119 (809/68030). AF 95% confidence interval is 0.0112. There are 5 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK1	NM_000037.4	MANE Select	c.1590C>T	p.Ala530Ala	synonymous	Exon 14 of 43	NP_000028.3
ANK1	NM_001142446.2		c.1689C>T	p.Ala563Ala	synonymous	Exon 14 of 43	NP_001135918.1	P16157-21
ANK1	NM_020476.3		c.1590C>T	p.Ala530Ala	synonymous	Exon 14 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.1590C>T	p.Ala530Ala	synonymous	Exon 14 of 43	ENSP00000289734.8	P16157-3
ANK1	ENST00000265709.14	TSL:1	c.1689C>T	p.Ala563Ala	synonymous	Exon 14 of 43	ENSP00000265709.8	P16157-21
ANK1	ENST00000347528.8	TSL:1	c.1590C>T	p.Ala530Ala	synonymous	Exon 14 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes

AF:

0.00644

AC:

980

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00611

AC:

1536

AN:

251220

AF XY:

0.00577

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.0111

AC:

16259

AN:

1461126

Hom.:

146

Cov.:

AF XY:

0.0106

AC XY:

7713

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33456

American (AMR)

AF:

0.00233

AC:

104

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000638

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00167

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00114

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.0139

AC:

15444

AN:

1111940

Other (OTH)

AF:

0.00728

AC:

439

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

998

1997

2995

3994

4992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.00643

AC:

980

AN:

152334

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

426

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41580

American (AMR)

AF:

0.00281

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

809

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00906

Hom.:

Bravo

AF:

0.00652

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.0117

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spherocytosis type 1 (2)

not provided (2)

not specified (1)

Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.6

(source)

DANN

Benign

0.80

PhyloP100

-0.10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over