rs6982971

Variant names:

• chr8-41725923-T-C
• rs6982971
• NM_000037.4:c.450A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.450A>G​(p.Val150Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,518 control chromosomes in the GnomAD database, including 2,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (174 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2470 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38
• Publications: 6 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 8-41725923-T-C is Benign according to our data. Variant chr8-41725923-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

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.450A>G	p.Val150Val	synonymous	Exon 6 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.549A>G	p.Val183Val	synonymous	Exon 6 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.450A>G	p.Val150Val	synonymous	Exon 6 of 42	NP_065209.2	P16157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.450A>G	p.Val150Val	synonymous	Exon 6 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.549A>G	p.Val183Val	synonymous	Exon 6 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.450A>G	p.Val150Val	synonymous	Exon 6 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0430 AC: 6553 AN: 152242 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0461 AC: 11400 AN: 247026 AF XY: 0.0433

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.0766

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0544 AC: 79425 AN: 1461158 Hom.: 2470 Cov.: 34 AF XY: 0.0525 AC XY: 38132 AN XY: 726862

African (AFR) AF: 0.0265 AC: 886 AN: 33470

American (AMR) AF: 0.0678 AC: 3032 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 694 AN: 26134

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39694

South Asian (SAS) AF: 0.0150 AC: 1294 AN: 86204

European-Finnish (FIN) AF: 0.0716 AC: 3809 AN: 53186

Middle Eastern (MID) AF: 0.0131 AC: 73 AN: 5552

European-Non Finnish (NFE) AF: 0.0600 AC: 66710 AN: 1111864

Other (OTH) AF: 0.0477 AC: 2880 AN: 60354

GnomAD4 genome AF: 0.0431 AC: 6566 AN: 152360 Hom.: 174 Cov.: 32 AF XY: 0.0423 AC XY: 3150 AN XY: 74494

African (AFR) AF: 0.0256 AC: 1065 AN: 41596

American (AMR) AF: 0.0405 AC: 620 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.00993 AC: 48 AN: 4832

European-Finnish (FIN) AF: 0.0766 AC: 814 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0556 AC: 3781 AN: 68026

Other (OTH) AF: 0.0369 AC: 78 AN: 2116

Alfa AF: 0.0490 Hom.: 139

Bravo AF: 0.0406

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0467

EpiControl AF: 0.0520

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6982971; hg19: chr8-41583441; COSMIC: COSV55897007;