chr8-41734016-C-G

Variant names:

• chr8-41734016-C-G
• rs61753680
• NM_000037.4:c.183G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000037.4(ANK1):​c.183G>C​(p.Val61Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.0188 in 1,614,130 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 33)
  • Exomes 𝑓: 0.019 (359 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.08
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 8-41734016-C-G is Benign according to our data. Variant chr8-41734016-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0126 (1913/152346) while in subpopulation SAS AF = 0.03 (145/4828). AF 95% confidence interval is 0.0261. There are 20 homozygotes in GnomAd4. There are 903 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	NM_000037.4	MANE Select	c.183G>C	p.Val61Val	synonymous	Exon 3 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.282G>C	p.Val94Val	synonymous	Exon 3 of 43	NP_001135918.1
	ANK1	NM_020476.3		c.183G>C	p.Val61Val	synonymous	Exon 3 of 42	NP_065209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK1	ENST00000289734.13	TSL:1 MANE Select	c.183G>C	p.Val61Val	synonymous	Exon 3 of 43	ENSP00000289734.8
	ANK1	ENST00000265709.14	TSL:1	c.282G>C	p.Val94Val	synonymous	Exon 3 of 43	ENSP00000265709.8
	ANK1	ENST00000347528.8	TSL:1	c.183G>C	p.Val61Val	synonymous	Exon 3 of 42	ENSP00000339620.4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1909 AN: 152228 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0157 AC: 3950 AN: 251490 AF XY: 0.0171

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00961

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0194 AC: 28366 AN: 1461784 Hom.: 359 Cov.: 31 AF XY: 0.0197 AC XY: 14353 AN XY: 727186

African (AFR) AF: 0.00230 AC: 77 AN: 33480

American (AMR) AF: 0.00691 AC: 309 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 420 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0327 AC: 2824 AN: 86248

European-Finnish (FIN) AF: 0.0102 AC: 544 AN: 53414

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.0208 AC: 23146 AN: 1111924

Other (OTH) AF: 0.0165 AC: 996 AN: 60394

GnomAD4 genome AF: 0.0126 AC: 1913 AN: 152346 Hom.: 20 Cov.: 33 AF XY: 0.0121 AC XY: 903 AN XY: 74494

African (AFR) AF: 0.00390 AC: 162 AN: 41582

American (AMR) AF: 0.00791 AC: 121 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4828

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1315 AN: 68038

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0166 Hom.: 13

Bravo AF: 0.0120

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 1 Benign:3

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spherocytosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=52/48	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: rs61753680; hg19: chr8-41591534;