dbSNP rs183894680: ANK1:c.127-39554G>A (chr8-41797691-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001142446.2(ANK1):c.127-39554G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,200,424 control chromosomes in the GnomAD database, including 209 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 0.016 ( 28 hom., cov: 32)

Exomes 𝑓: 0.018 ( 181 hom. )

Consequence

ANK1
NM_001142446.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:2

Conservation

PhyloP100: -0.289

Publications

4 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:

ENSG00000289514 (HGNC:):

ENSG00000289514 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 8-41797691-C-T is Benign according to our data. Variant chr8-41797691-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 512.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2438/152206) while in subpopulation NFE AF = 0.0182 (1238/67994). AF 95% confidence interval is 0.0174. There are 28 homozygotes in GnomAd4. There are 1139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
ANK1	NM_001142446.2		c.127-39554G>A	intron	N/A	NP_001135918.1	P16157-21
ANK1	NM_000037.4	MANE Select	c.-153G>A	upstream_gene	N/A	NP_000028.3
ANK1	NM_020476.3		c.-153G>A	upstream_gene	N/A	NP_065209.2	P16157-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANK1	ENST00000265709.14	TSL:1	c.127-39554G>A	intron	N/A	ENSP00000265709.8	P16157-21
ANK1	ENST00000705521.1		c.127-39554G>A	intron	N/A	ENSP00000516136.1	A0A994J4W8
ANK1	ENST00000289734.13	TSL:1 MANE Select	c.-153G>A	upstream_gene	N/A	ENSP00000289734.8	P16157-3

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2426

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.00860

GnomAD4 exome

AF:

0.0185

AC:

19358

AN:

1048218

Hom.:

181

AF XY:

0.0180

AC XY:

9183

AN XY:

511456

show subpopulations

African (AFR)

AF:

0.0210

AC:

422

AN:

20140

American (AMR)

AF:

0.00975

AC:

125

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

AN:

15708

East Asian (EAS)

AF:

0.0000363

AC:

AN:

27582

South Asian (SAS)

AF:

0.00310

AC:

142

AN:

45866

European-Finnish (FIN)

AF:

0.0180

AC:

749

AN:

41636

Middle Eastern (MID)

AF:

0.00230

AC:

AN:

3044

European-Non Finnish (NFE)

AF:

0.0204

AC:

17086

AN:

837586

Other (OTH)

AF:

0.0170

AC:

743

AN:

43830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

891

1783

2674

3566

4457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.0160

AC:

2438

AN:

152206

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1139

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0179

AC:

746

AN:

41574

American (AMR)

AF:

0.0131

AC:

201

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000196

AC:

AN:

5100

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0190

AC:

202

AN:

10616

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0182

AC:

1238

AN:

67994

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0165

Hom.:

Bravo

AF:

0.0162

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.3

(source)

DANN

Benign

0.88

PhyloP100

-0.29

PromoterAI

-0.069

Neutral

(source)

Mutation Taster

=100/0

disease causing (ClinVar)

(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