rs558889

Variant names:

• chr8-41713915-C-T
• rs558889
• NM_000037.4:c.1800+241G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001142446.2(ANK1):​c.1899+241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,056 control chromosomes in the GnomAD database, including 8,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (8634 hom., cov: 33)
• Consequence: ANK1 NM_001142446.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.255
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-41713915-C-T is Benign according to our data. Variant chr8-41713915-C-T is described in ClinVar as Benign. ClinVar VariationId is 1282486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.1800+241G>A		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.1899+241G>A		intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.1800+241G>A		intron	N/A	NP_065209.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.1800+241G>A		intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.1899+241G>A		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.1800+241G>A		intron	N/A	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47831 AN: 151938 Hom.: 8631 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.337

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47846 AN: 152056 Hom.: 8634 Cov.: 33 AF XY: 0.323 AC XY: 24027 AN XY: 74312

African (AFR) AF: 0.154 AC: 6391 AN: 41470

American (AMR) AF: 0.400 AC: 6115 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3472

East Asian (EAS) AF: 0.648 AC: 3349 AN: 5168

South Asian (SAS) AF: 0.358 AC: 1724 AN: 4818

European-Finnish (FIN) AF: 0.370 AC: 3904 AN: 10556

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24271 AN: 67980

Other (OTH) AF: 0.335 AC: 707 AN: 2112

Alfa AF: 0.340 Hom.: 6932

Bravo AF: 0.313

Asia WGS AF: 0.428 AC: 1488 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.66
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs558889; hg19: chr8-41571433;