rs183894680

Positions:

• chr8-41797691-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000265709.14(ANK1):​c.127-39554G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,200,424 control chromosomes in the GnomAD database, including 209 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 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.018 (181 hom.)
• Consequence: ANK1 ENST00000265709.14 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: -0.289

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-41797691-C-T is Benign according to our data. Variant chr8-41797691-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 512.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2438/152206) while in subpopulation NFE AF= 0.0182 (1238/67994). AF 95% confidence interval is 0.0174. There are 28 homozygotes in gnomad4. There are 1139 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_001142446.2	c.127-39554G>A		intron_variant			NP_001135918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000265709.14	c.127-39554G>A		intron_variant		1		ENSP00000265709	P4
ANK1	ENST00000705521.1	c.127-39554G>A		intron_variant				ENSP00000516136	A2

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2426 AN: 152090 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0185 AC: 19358 AN: 1048218 Hom.: 181 AF XY: 0.0180 AC XY: 9183 AN XY: 511456

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00975

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.0000363

Gnomad4 SAS exome AF: 0.00310

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0160 AC: 2438 AN: 152206 Hom.: 28 Cov.: 32 AF XY: 0.0153 AC XY: 1139 AN XY: 74398

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0167 Hom.: 4

Bravo AF: 0.0162

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spherocytosis, type 1, autosomal recessive Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_012820.1(NM_001142446.2):c.127-39554G>A in the ANK1 gene has an allele frequency of 0.02 in African subpopulation in the gnomAD database. 6 homozygous occurrences are observed in the gnomAD database. This variant was reported as -153G-A in a hereditary spherocytosis patient (PMID: 11102985). Benign computational verdict because benign prediction from DANN. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2, BP4. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ANK1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 19, 2023	BS1, BS2, BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.3
DANN	Benign	0.88

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: rs183894680; hg19: chr8-41655209;