rs2304880

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 261299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41702091-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.2349C>T	p.Thr783Thr	synonymous_variant	21/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.2349C>T	p.Thr783Thr	synonymous_variant	21/43	1	NM_000037.4	ENSP00000289734.8

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

GnomAD3 exomes AF: 0.259 AC: 65077 AN: 251288 Hom.: 9426 AF XY: 0.264 AC XY: 35925 AN XY: 135834

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 SAS exome AF: 0.319

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

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.0823

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.258

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

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.0710

Gnomad4 SAS AF: 0.308

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.223

Alfa AF: 0.246 Hom.: 6204

Bravo AF: 0.195

Asia WGS AF: 0.221 AC: 769 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.266

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Spherocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.4
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304880; hg19: chr8-41559609; COSMIC: COSV55882446; COSMIC: COSV55882446;