rs2304873

Positions:

• chr8-41725776-C-T

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.597G>A​(p.Pro199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,609,872 control chromosomes in the GnomAD database, including 15,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1149 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14332 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.42

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=-0.56).
• BP6: Variant 8-41725776-C-T is Benign according to our data. Variant chr8-41725776-C-T is described in ClinVar as [Benign]. Clinvar id is 261319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41725776-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.597G>A	p.Pro199Pro	synonymous_variant	6/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.597G>A	p.Pro199Pro	synonymous_variant	6/43	1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16716 AN: 152140 Hom.: 1148 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.133 AC: 32316 AN: 243386 Hom.: 2308 AF XY: 0.138 AC XY: 18319 AN XY: 132356

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.137 AC: 199591 AN: 1457614 Hom.: 14332 Cov.: 34 AF XY: 0.140 AC XY: 101225 AN XY: 725062

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.110 AC: 16713 AN: 152258 Hom.: 1149 Cov.: 33 AF XY: 0.112 AC XY: 8354 AN XY: 74436

Gnomad4 AFR AF: 0.0329

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.126

Alfa AF: 0.129 Hom.: 712

Bravo AF: 0.104

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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 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	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

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 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	-0.56
CADD	Benign	0.56
DANN	Benign	0.95
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: rs2304873; hg19: chr8-41583294; COSMIC: COSV55874582;