chr8-41690323-C-T

Variant names:

• chr8-41690323-C-T
• rs147536061
• NM_000037.4:c.4008G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6 BP7 BS1 BS2

The NM_000037.4(ANK1):​c.4008G>A​(p.Pro1336Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,614,230 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 33)
  • Exomes 𝑓: 0.017 (268 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.38
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.249).
• BP6: Variant 8-41690323-C-T is Benign according to our data. Variant chr8-41690323-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261308.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1947/152340) while in subpopulation NFE AF = 0.0203 (1381/68024). AF 95% confidence interval is 0.0194. There are 25 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.4008G>A	p.Pro1336Pro	synonymous	Exon 33 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.4131G>A	p.Pro1377Pro	synonymous	Exon 34 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.4008G>A	p.Pro1336Pro	synonymous	Exon 33 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.4008G>A	p.Pro1336Pro	synonymous	Exon 33 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.4131G>A	p.Pro1377Pro	synonymous	Exon 34 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.4008G>A	p.Pro1336Pro	synonymous	Exon 33 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1947 AN: 152222 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0129 AC: 3240 AN: 251492 AF XY: 0.0133

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00952

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0169 AC: 24663 AN: 1461890 Hom.: 268 Cov.: 33 AF XY: 0.0166 AC XY: 12073 AN XY: 727246

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00306 AC: 137 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00964 AC: 252 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00423 AC: 365 AN: 86258

European-Finnish (FIN) AF: 0.0256 AC: 1369 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0195 AC: 21682 AN: 1112008

Other (OTH) AF: 0.0126 AC: 761 AN: 60396

GnomAD4 genome AF: 0.0128 AC: 1947 AN: 152340 Hom.: 25 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74502

African (AFR) AF: 0.00317 AC: 132 AN: 41582

American (AMR) AF: 0.00555 AC: 85 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0270 AC: 287 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0203 AC: 1381 AN: 68024

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0138 Hom.: 15

Bravo AF: 0.0106

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0180

EpiControl AF: 0.0174

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.88
DANN	Benign	0.67
PhyloP100		-1.4
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)		0.010		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: rs147536061; hg19: chr8-41547841;