rs61735313

Positions:

• chr8-41724513-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000037.4(ANK1):​c.654C>A​(p.Asn218Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0172 in 1,602,132 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (284 hom.)
• Consequence: ANK1 NM_000037.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.61

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.009991944).
• BP6: Variant 8-41724513-G-T is Benign according to our data. Variant chr8-41724513-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 261321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41724513-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1878/152324) while in subpopulation NFE AF= 0.0204 (1391/68034). AF 95% confidence interval is 0.0196. There are 18 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK1	NM_000037.4	c.654C>A	p.Asn218Lys	missense_variant	7/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13	c.654C>A	p.Asn218Lys	missense_variant	7/43	1	NM_000037.4	A2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1878 AN: 152206 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00342

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0115 AC: 2651 AN: 229782 Hom.: 25 AF XY: 0.0117 AC XY: 1445 AN XY: 123916

Gnomad AFR exome AF: 0.00360

Gnomad AMR exome AF: 0.00595

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0177 AC: 25716 AN: 1449808 Hom.: 284 Cov.: 32 AF XY: 0.0172 AC XY: 12346 AN XY: 719822

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.00643

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00324

Gnomad4 FIN exome AF: 0.00644

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0123 AC: 1878 AN: 152324 Hom.: 18 Cov.: 32 AF XY: 0.0110 AC XY: 820 AN XY: 74484

Gnomad4 AFR AF: 0.00341

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00584

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0190 Hom.: 50

Bravo AF: 0.0122

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0108 AC: 1305

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.76	N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.77
MutPred		0.67		Gain of ubiquitination at N218 (P = 0.0494);Gain of ubiquitination at N218 (P = 0.0494);.;
MPC		2.0
ClinPred		0.031	T
GERP RS		5.5
Varity_R		0.77
gMVP		0.89

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: rs61735313; hg19: chr8-41582031;