rs2304880

Variant names:

• chr8-41702091-G-A
• rs2304880
• NM_000037.4:c.2349C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-41702091-G-A
• chr8-41702091-G-C

Variant summary

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

The NM_000037.4(ANK1):​c.2349C>T​(p.Thr783Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,882 control chromosomes in the GnomAD database, including 57,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4343 hom., cov: 33)
  • Exomes 𝑓: 0.26 (52962 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.976
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-41702091-G-A is Benign according to our data. Variant chr8-41702091-G-A is described in ClinVar as Benign. ClinVar VariationId is 261299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000037.4. 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.2349C>T	p.Thr783Thr	synonymous	Exon 21 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.2448C>T	p.Thr816Thr	synonymous	Exon 21 of 43	NP_001135918.1
	ANK1	NM_020476.3		c.2349C>T	p.Thr783Thr	synonymous	Exon 21 of 42	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.2349C>T	p.Thr783Thr	synonymous	Exon 21 of 43	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.2448C>T	p.Thr816Thr	synonymous	Exon 21 of 43	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.2349C>T	p.Thr783Thr	synonymous	Exon 21 of 42	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32034 AN: 152136 Hom.: 4338 Cov.: 33

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.259 AC: 65077 AN: 251288 AF XY: 0.264

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.297

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.0680

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.263 AC: 384291 AN: 1461628 Hom.: 52962 Cov.: 35 AF XY: 0.265 AC XY: 192933 AN XY: 727118

African (AFR) AF: 0.0464 AC: 1552 AN: 33480

American (AMR) AF: 0.293 AC: 13082 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8032 AN: 26132

East Asian (EAS) AF: 0.0823 AC: 3268 AN: 39700

South Asian (SAS) AF: 0.314 AC: 27081 AN: 86256

European-Finnish (FIN) AF: 0.343 AC: 18292 AN: 53370

Middle Eastern (MID) AF: 0.256 AC: 1476 AN: 5768

European-Non Finnish (NFE) AF: 0.266 AC: 295948 AN: 1111820

Other (OTH) AF: 0.258 AC: 15560 AN: 60384

GnomAD4 genome AF: 0.210 AC: 32042 AN: 152254 Hom.: 4343 Cov.: 33 AF XY: 0.214 AC XY: 15946 AN XY: 74428

African (AFR) AF: 0.0548 AC: 2279 AN: 41590

American (AMR) AF: 0.259 AC: 3956 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1060 AN: 3470

East Asian (EAS) AF: 0.0710 AC: 368 AN: 5182

South Asian (SAS) AF: 0.308 AC: 1486 AN: 4822

European-Finnish (FIN) AF: 0.354 AC: 3745 AN: 10584

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18350 AN: 68004

Other (OTH) AF: 0.223 AC: 470 AN: 2112

Alfa AF: 0.242 Hom.: 7551

Bravo AF: 0.195

Asia WGS AF: 0.221 AC: 769 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.266

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spherocytosis type 1 (5)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.4
DANN	Benign	0.79
PhyloP100		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2304880; hg19: chr8-41559609; COSMIC: COSV55882446; COSMIC: COSV55882446;