8-41661730-T-C

Variant names:

• chr8-41661730-T-C
• rs516946
• ENST00000524227.5:n.3084A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000524227.5(ANK1):​n.3084A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,602,982 control chromosomes in the GnomAD database, including 474,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45020 hom., cov: 31)
  • Exomes 𝑓: 0.77 (428999 hom.)
• Consequence: ANK1 ENST00000524227.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.142
• Publications: 124 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

ENSG00000253389 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-41661730-T-C is Benign according to our data. Variant chr8-41661730-T-C is described in ClinVar as Benign. ClinVar VariationId is 1262189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4	c.5544+146A>G		intron_variant	Intron 41 of 42	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.5544+146A>G		intron_variant	Intron 41 of 42	1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116821 AN: 151990 Hom.: 44969 Cov.: 31

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.749

GnomAD2 exomes AF: 0.783 AC: 191940 AN: 245252 AF XY: 0.781

Gnomad AFR exome AF: 0.774

Gnomad AMR exome AF: 0.810

Gnomad ASJ exome AF: 0.710

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.761

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.768 AC: 1114432 AN: 1450876 Hom.: 428999 Cov.: 46 AF XY: 0.768 AC XY: 554815 AN XY: 722458

African (AFR) AF: 0.780 AC: 25986 AN: 33336

American (AMR) AF: 0.805 AC: 35976 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18554 AN: 26108

East Asian (EAS) AF: 0.863 AC: 34220 AN: 39674

South Asian (SAS) AF: 0.800 AC: 68924 AN: 86104

European-Finnish (FIN) AF: 0.795 AC: 38099 AN: 47908

Middle Eastern (MID) AF: 0.719 AC: 4140 AN: 5756

European-Non Finnish (NFE) AF: 0.761 AC: 842076 AN: 1107114

Other (OTH) AF: 0.772 AC: 46457 AN: 60162

GnomAD4 genome AF: 0.769 AC: 116929 AN: 152106 Hom.: 45020 Cov.: 31 AF XY: 0.769 AC XY: 57190 AN XY: 74374

African (AFR) AF: 0.777 AC: 32221 AN: 41490

American (AMR) AF: 0.748 AC: 11437 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2449 AN: 3468

East Asian (EAS) AF: 0.871 AC: 4489 AN: 5154

South Asian (SAS) AF: 0.802 AC: 3864 AN: 4818

European-Finnish (FIN) AF: 0.798 AC: 8462 AN: 10600

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.760 AC: 51647 AN: 67976

Other (OTH) AF: 0.752 AC: 1586 AN: 2110

Alfa AF: 0.760 Hom.: 175660

Bravo AF: 0.764

Asia WGS AF: 0.865 AC: 3010 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.19
DANN	Benign	0.37
PhyloP100		-0.14
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: rs516946; hg19: chr8-41519248;