rs10090395

Variant names:

• chr8-41809356-T-C
• rs10090395
• ENST00000265709.14:c.127-51219A>G

Variant summary

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

The NM_001142446.2(ANK1):​c.127-51219A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,156 control chromosomes in the GnomAD database, including 7,011 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 0.29 (7011 hom., cov: 33)
• Consequence: ANK1 NM_001142446.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• 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: 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.418 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_001142446.2		c.127-51219A>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.127-51219A>G		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000705521.1		c.127-51219A>G		intron	N/A	ENSP00000516136.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44549 AN: 152036 Hom.: 7003 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.293 AC: 44560 AN: 152156 Hom.: 7011 Cov.: 33 AF XY: 0.291 AC XY: 21621 AN XY: 74386

African (AFR) AF: 0.210 AC: 8726 AN: 41494

American (AMR) AF: 0.426 AC: 6523 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1255 AN: 3472

East Asian (EAS) AF: 0.116 AC: 602 AN: 5188

South Asian (SAS) AF: 0.378 AC: 1821 AN: 4814

European-Finnish (FIN) AF: 0.215 AC: 2282 AN: 10590

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.327 AC: 22256 AN: 67992

Other (OTH) AF: 0.342 AC: 721 AN: 2108

Alfa AF: 0.315 Hom.: 3261

Bravo AF: 0.306

Asia WGS AF: 0.249 AC: 865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.058
DANN	Benign	0.30
PhyloP100		-1.4
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: rs10090395; hg19: chr8-41666874;