chr8-41836250-T-A

Variant names:

• chr8-41836250-T-A
• rs906290
• ENST00000265709.14:c.126+60105A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142446.2(ANK1):​c.126+60105A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 152,182 control chromosomes in the GnomAD database, including 14,774 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14774 hom., cov: 33)
• Consequence: ANK1 NM_001142446.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 1 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 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_001142446.2		c.126+60105A>T		intron	N/A	NP_001135918.1	P16157-21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000265709.14	TSL:1	c.126+60105A>T		intron	N/A	ENSP00000265709.8	P16157-21
	ANK1	ENST00000705521.1		c.126+60105A>T		intron	N/A	ENSP00000516136.1	A0A994J4W8

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65398 AN: 152064 Hom.: 14745 Cov.: 33

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.430 AC: 65480 AN: 152182 Hom.: 14774 Cov.: 33 AF XY: 0.439 AC XY: 32662 AN XY: 74396

African (AFR) AF: 0.493 AC: 20444 AN: 41506

American (AMR) AF: 0.360 AC: 5504 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1335 AN: 3468

East Asian (EAS) AF: 0.786 AC: 4066 AN: 5174

South Asian (SAS) AF: 0.404 AC: 1954 AN: 4832

European-Finnish (FIN) AF: 0.500 AC: 5302 AN: 10600

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

European-Non Finnish (NFE) AF: 0.377 AC: 25660 AN: 67992

Other (OTH) AF: 0.420 AC: 887 AN: 2114

Alfa AF: 0.411 Hom.: 1635

Bravo AF: 0.424

Asia WGS AF: 0.610 AC: 2120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.51
DANN	Benign	0.53
PhyloP100		-0.61
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: rs906290; hg19: chr8-41693768;