chr8-41757620-G-A

Variant names:

• chr8-41757620-G-A
• rs7006290
• NM_000037.4:c.129+416C>T

Variant summary

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

The ENST00000289734.13(ANK1):​c.129+416C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,050 control chromosomes in the GnomAD database, including 7,384 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 0.31 (7384 hom., cov: 33)
• Consequence: ANK1 ENST00000289734.13 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 8 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 (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000289734.13. 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_000037.4	MANE Select	c.129+416C>T		intron	N/A	NP_000028.3
	ANK1	NM_001142446.2		c.228+416C>T		intron	N/A	NP_001135918.1
	ANK1	NM_020476.3		c.129+416C>T		intron	N/A	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.129+416C>T		intron	N/A	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.228+416C>T		intron	N/A	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.129+416C>T		intron	N/A	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46699 AN: 151932 Hom.: 7376 Cov.: 33

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.307 AC: 46733 AN: 152050 Hom.: 7384 Cov.: 33 AF XY: 0.311 AC XY: 23093 AN XY: 74330

African (AFR) AF: 0.271 AC: 11253 AN: 41470

American (AMR) AF: 0.259 AC: 3965 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1505 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5166

South Asian (SAS) AF: 0.348 AC: 1676 AN: 4822

European-Finnish (FIN) AF: 0.430 AC: 4545 AN: 10560

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21574 AN: 67960

Other (OTH) AF: 0.321 AC: 679 AN: 2112

Alfa AF: 0.317 Hom.: 22553

Bravo AF: 0.290

Asia WGS AF: 0.314 AC: 1089 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	0.092
DANN	Benign	0.75
PhyloP100		-1.2
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: rs7006290; hg19: chr8-41615138;