rs61735313

Variant names:

• chr8-41724513-G-T
• rs61735313
• NM_000037.4:c.654C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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:7
• Conservation: PhyloP100: 3.61
• Publications: 13 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=0.009991944).
• BP6: Variant 8-41724513-G-T is Benign according to our data. Variant chr8-41724513-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000037.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.654C>A	p.Asn218Lys	missense	Exon 7 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.753C>A	p.Asn251Lys	missense	Exon 7 of 43	NP_001135918.1
	ANK1	NM_020476.3		c.654C>A	p.Asn218Lys	missense	Exon 7 of 42	NP_065209.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.654C>A	p.Asn218Lys	missense	Exon 7 of 43	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.753C>A	p.Asn251Lys	missense	Exon 7 of 43	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.654C>A	p.Asn218Lys	missense	Exon 7 of 42	ENSP00000339620.4

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

GnomAD2 exomes AF: 0.0115 AC: 2651 AN: 229782 AF XY: 0.0117

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 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

African (AFR) AF: 0.00342 AC: 114 AN: 33320

American (AMR) AF: 0.00643 AC: 278 AN: 43268

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 324 AN: 25834

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39390

South Asian (SAS) AF: 0.00324 AC: 271 AN: 83730

European-Finnish (FIN) AF: 0.00644 AC: 338 AN: 52446

Middle Eastern (MID) AF: 0.0159 AC: 89 AN: 5598

European-Non Finnish (NFE) AF: 0.0212 AC: 23476 AN: 1106268

Other (OTH) AF: 0.0138 AC: 825 AN: 59954

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

African (AFR) AF: 0.00341 AC: 142 AN: 41582

American (AMR) AF: 0.0102 AC: 156 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0204 AC: 1391 AN: 68034

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0184 Hom.: 98

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spherocytosis type 1 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.76	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.77
MutPred		0.67		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
Mutation Taster		=97/3	polymorphism

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: rs61735313; hg19: chr8-41582031;