rs6982971

chr8-41725923-T-C

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.450A>G(p.Val150=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,518 control chromosomes in the GnomAD database, including 2,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (174 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2470 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.38

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=-0.58).
• BP6: Variant 8-41725923-T-C is Benign according to our data. Variant chr8-41725923-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41725923-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.450A>G	p.Val150=	synonymous_variant	6/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.450A>G	p.Val150=	synonymous_variant	6/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0430 AC: 6553 AN: 152242 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0461 AC: 11400 AN: 247026 Hom.: 345 AF XY: 0.0433 AC XY: 5812 AN XY: 134098

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0766

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0544 AC: 79425 AN: 1461158 Hom.: 2470 Cov.: 34 AF XY: 0.0525 AC XY: 38132 AN XY: 726862

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.0678

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0716

Gnomad4 NFE exome AF: 0.0600

Gnomad4 OTH exome AF: 0.0477

GnomAD4 genome AF: 0.0431 AC: 6566 AN: 152360 Hom.: 174 Cov.: 32 AF XY: 0.0423 AC XY: 3150 AN XY: 74494

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00993

Gnomad4 FIN AF: 0.0766

Gnomad4 NFE AF: 0.0556

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0497 Hom.: 126

Bravo AF: 0.0406

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0467

EpiControl AF: 0.0520

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Spherocytosis Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	12
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6982971; hg19: chr8-41583441; COSMIC: COSV55897007;