NM_000037.4:c.1856G>A

Variant names:

• chr8-41708920-C-T
• rs2304877
• NM_000037.4:c.1856G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000037.4(ANK1):​c.1856G>A​(p.Arg619His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,614,060 control chromosomes in the GnomAD database, including 2,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (202 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2022 hom.)
• Consequence: ANK1 NM_000037.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.64
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hereditary spherocytosis type 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045528114).
• BP6: Variant 8-41708920-C-T is Benign according to our data. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41708920-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4	c.1856G>A	p.Arg619His	missense_variant	Exon 17 of 43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.1856G>A	p.Arg619His	missense_variant	Exon 17 of 43	1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7166 AN: 152122 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0367

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0444 AC: 11169 AN: 251420 AF XY: 0.0409

Gnomad AFR exome AF: 0.0534

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.0374

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0394

GnomAD4 exome AF: 0.0501 AC: 73275 AN: 1461820 Hom.: 2022 Cov.: 32 AF XY: 0.0483 AC XY: 35118 AN XY: 727222

African (AFR) AF: 0.0596 AC: 1997 AN: 33480

American (AMR) AF: 0.0669 AC: 2991 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 685 AN: 26136

East Asian (EAS) AF: 0.0473 AC: 1877 AN: 39700

South Asian (SAS) AF: 0.0151 AC: 1300 AN: 86258

European-Finnish (FIN) AF: 0.0395 AC: 2110 AN: 53354

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5764

European-Non Finnish (NFE) AF: 0.0536 AC: 59617 AN: 1112008

Other (OTH) AF: 0.0433 AC: 2615 AN: 60396

GnomAD4 genome AF: 0.0472 AC: 7183 AN: 152240 Hom.: 202 Cov.: 32 AF XY: 0.0454 AC XY: 3379 AN XY: 74448

African (AFR) AF: 0.0547 AC: 2271 AN: 41536

American (AMR) AF: 0.0410 AC: 627 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5170

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4830

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3367 AN: 68002

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0475 Hom.: 283

Bravo AF: 0.0484

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.0547 AC: 241

ESP6500EA AF: 0.0488 AC: 420

ExAC AF: 0.0435 AC: 5283

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10745622) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spherocytosis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;L;.
PhyloP100		2.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.099	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.020	B;B;B
Vest4		0.13
MPC		0.37
ClinPred		0.0078	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.27
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304877; hg19: chr8-41566438; COSMIC: COSV55882618; COSMIC: COSV55882618;