8-41696410-C-G

Variant names:

• chr8-41696410-C-G
• rs504574
• NM_000037.4:c.2913G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000037.4(ANK1):​c.2913G>C​(p.Leu971Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,058 control chromosomes in the GnomAD database, including 178,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13836 hom., cov: 33)
  • Exomes 𝑓: 0.47 (164922 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.13
• Publications: 19 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.212).
• BP6: Variant 8-41696410-C-G is Benign according to our data. Variant chr8-41696410-C-G is described in ClinVar as Benign. ClinVar VariationId is 261301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 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.2913G>C	p.Leu971Leu	synonymous	Exon 26 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.3036G>C	p.Leu1012Leu	synonymous	Exon 27 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.2913G>C	p.Leu971Leu	synonymous	Exon 26 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.2913G>C	p.Leu971Leu	synonymous	Exon 26 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.3036G>C	p.Leu1012Leu	synonymous	Exon 27 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.2913G>C	p.Leu971Leu	synonymous	Exon 26 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60093 AN: 152022 Hom.: 13834 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.485 AC: 120957 AN: 249342 AF XY: 0.487

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.603

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.539

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.470 AC: 686948 AN: 1460918 Hom.: 164922 Cov.: 85 AF XY: 0.472 AC XY: 343014 AN XY: 726788

African (AFR) AF: 0.129 AC: 4317 AN: 33474

American (AMR) AF: 0.590 AC: 26381 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 11179 AN: 26114

East Asian (EAS) AF: 0.527 AC: 20901 AN: 39688

South Asian (SAS) AF: 0.505 AC: 43593 AN: 86246

European-Finnish (FIN) AF: 0.555 AC: 29254 AN: 52708

Middle Eastern (MID) AF: 0.412 AC: 2369 AN: 5756

European-Non Finnish (NFE) AF: 0.468 AC: 520887 AN: 1111846

Other (OTH) AF: 0.465 AC: 28067 AN: 60376

GnomAD4 genome AF: 0.395 AC: 60100 AN: 152140 Hom.: 13836 Cov.: 33 AF XY: 0.406 AC XY: 30182 AN XY: 74388

African (AFR) AF: 0.144 AC: 5978 AN: 41552

American (AMR) AF: 0.506 AC: 7739 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1513 AN: 3470

East Asian (EAS) AF: 0.514 AC: 2645 AN: 5146

South Asian (SAS) AF: 0.509 AC: 2450 AN: 4818

European-Finnish (FIN) AF: 0.578 AC: 6125 AN: 10596

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32130 AN: 67948

Other (OTH) AF: 0.417 AC: 881 AN: 2112

Alfa AF: 0.372 Hom.: 1985

Bravo AF: 0.381

Asia WGS AF: 0.506 AC: 1759 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.467

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spherocytosis type 1 (5)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spherocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.6
DANN	Benign	0.68
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs504574; hg19: chr8-41553928; COSMIC: COSV55880303; COSMIC: COSV55880303;