8-41668396-C-T

Position:

chr8-41668396-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000037.4(ANK1):c.5265G>A(p.Val1755=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,614,112 control chromosomes in the GnomAD database, including 45,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4040 hom., cov: 33)

Exomes 𝑓: 0.23 ( 41142 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.27

Variant links:

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]

ANK1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 8-41668396-C-T is Benign according to our data. Variant chr8-41668396-C-T is described in ClinVar as [Benign]. Clinvar id is 261316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41668396-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4 linkuse as main transcript	c.5265G>A	p.Val1755=	synonymous_variant	39/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13 linkuse as main transcript	c.5265G>A	p.Val1755=	synonymous_variant	39/43	1	NM_000037.4	ENSP00000289734	A2	P16157-3

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34461

AN:

152128

Hom.:

4030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.376

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.201

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.249

GnomAD3 exomes

AF:

0.217

AC:

54591

AN:

251474

Hom.:

6278

AF XY:

0.219

AC XY:

29806

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.124

Gnomad SAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.234

AC:

342714

AN:

1461866

Hom.:

41142

Cov.:

AF XY:

0.235

AC XY:

170673

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.202

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.288

Gnomad4 EAS exome

AF:

0.131

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.206

Gnomad4 NFE exome

AF:

0.243

Gnomad4 OTH exome

AF:

0.232

GnomAD4 genome

AF:

0.227

AC:

34492

AN:

152246

Hom.:

4040

Cov.:

AF XY:

0.227

AC XY:

16879

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.199

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.292

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.199

Gnomad4 FIN

AF:

0.201

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.246

Alfa

AF:

0.241

Hom.:

8938

Bravo

AF:

0.231

Asia WGS

AF:

0.141

AC:

490

AN:

3478

EpiCase

AF:

0.265

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Oct 10, 2014	- -

not provided

Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

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

-0.74

CADD

Benign

2.1

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over