rs2304871

Positions:

• chr8-41727920-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.315C>T​(p.Asn105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,572 control chromosomes in the GnomAD database, including 58,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4494 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53628 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.714

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-41727920-G-A is Benign according to our data. Variant chr8-41727920-G-A is described in ClinVar as [Benign]. Clinvar id is 261304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41727920-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.714 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.315C>T	p.Asn105=	synonymous_variant	4/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.315C>T	p.Asn105=	synonymous_variant	4/43	1	NM_000037.4	ENSP00000289734	A2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36345 AN: 152010 Hom.: 4488 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.241 AC: 60622 AN: 251384 Hom.: 7842 AF XY: 0.249 AC XY: 33812 AN XY: 135870

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.268 AC: 391016 AN: 1461444 Hom.: 53628 Cov.: 41 AF XY: 0.269 AC XY: 195343 AN XY: 727058

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.239 AC: 36357 AN: 152128 Hom.: 4494 Cov.: 32 AF XY: 0.236 AC XY: 17531 AN XY: 74346

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.259

Alfa AF: 0.261 Hom.: 4111

Bravo AF: 0.238

Asia WGS AF: 0.232 AC: 806 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.296

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Spherocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.80
CADD	Benign	1.7
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2304871; hg19: chr8-41585438; COSMIC: COSV55881854;