8-41696410-C-G

Position:

• chr8-41696410-C-G

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.2913G>C​(p.Leu971=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,058 control chromosomes in the GnomAD database, including 178,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13836 hom., cov: 33)
  • Exomes 𝑓: 0.47 (164922 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.13

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=-0.5).
• BP6: Variant 8-41696410-C-G is Benign according to our data. Variant chr8-41696410-C-G is described in ClinVar as [Benign]. Clinvar id is 261301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41696410-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.2913G>C	p.Leu971=	synonymous_variant	26/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.2913G>C	p.Leu971=	synonymous_variant	26/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60093 AN: 152022 Hom.: 13834 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.485 AC: 120957 AN: 249342 Hom.: 30707 AF XY: 0.487 AC XY: 65883 AN XY: 135236

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.603

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.539

Gnomad SAS exome AF: 0.509

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.470 AC: 686948 AN: 1460918 Hom.: 164922 Cov.: 85 AF XY: 0.472 AC XY: 343014 AN XY: 726788

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.465

GnomAD4 genome AF: 0.395 AC: 60100 AN: 152140 Hom.: 13836 Cov.: 33 AF XY: 0.406 AC XY: 30182 AN XY: 74388

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.509

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.417

Alfa AF: 0.372 Hom.: 1985

Bravo AF: 0.381

Asia WGS AF: 0.506 AC: 1759 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.467

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

not provided Benign:2

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

-

- -

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	-0.50
CADD	Benign	6.6
DANN	Benign	0.68
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: rs504574; hg19: chr8-41553928; COSMIC: COSV55880303; COSMIC: COSV55880303;