8-41822335-T-C

Variant names:

• chr8-41822335-T-C
• rs4466386
• ENST00000265709.14:c.127-64198A>G

Variant summary

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

The ENST00000265709.14(ANK1):​c.127-64198A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,102 control chromosomes in the GnomAD database, including 43,486 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 0.75 (43486 hom., cov: 31)
• Consequence: ANK1 ENST00000265709.14 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.274
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265709.14. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_001142446.2		c.127-64198A>G		intron	N/A	NP_001135918.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000265709.14	TSL:1	c.127-64198A>G		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000705521.1		c.127-64198A>G		intron	N/A	ENSP00000516136.1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113926 AN: 151984 Hom.: 43474 Cov.: 31

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.760

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

GnomAD4 genome AF: 0.749 AC: 113992 AN: 152102 Hom.: 43486 Cov.: 31 AF XY: 0.742 AC XY: 55165 AN XY: 74340

African (AFR) AF: 0.790 AC: 32760 AN: 41488

American (AMR) AF: 0.768 AC: 11732 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2612 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1539 AN: 5166

South Asian (SAS) AF: 0.771 AC: 3711 AN: 4816

European-Finnish (FIN) AF: 0.688 AC: 7263 AN: 10562

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51908 AN: 67998

Other (OTH) AF: 0.761 AC: 1608 AN: 2112

Alfa AF: 0.752 Hom.: 11138

Bravo AF: 0.754

Asia WGS AF: 0.600 AC: 2092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		-0.27
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: rs4466386; hg19: chr8-41679853;