Genetic Variant ANK1:p.Val1755Val (chr8-41668396-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001142446.2(ANK1):c.5388G>A(p.Val1796Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,614,112 control chromosomes in the GnomAD database, including 45,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4040 hom., cov: 33)

Exomes 𝑓: 0.23 ( 41142 hom. )

Consequence

ANK1
NM_001142446.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

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

ANK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.029).

BP6

Variant 8-41668396-C-T is Benign according to our data. Variant chr8-41668396-C-T is described in ClinVar as Benign. ClinVar VariationId is 261316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142446.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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
ANK1	NM_020476.3		c.5265G>A	p.Val1755Val	synonymous	Exon 39 of 42	NP_065209.2

Ensembl Transcripts

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

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

Alfa

AF:

0.238

Hom.:

13217

Bravo

AF:

0.231

Asia WGS

AF:

0.141

AC:

490

AN:

3478

EpiCase

AF:

0.265

EpiControl

AF:

0.260

ClinVar

ClinVar submissions as Germline

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 (1)

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

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

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