chr8-41714174-G-T

Variant names:

• chr8-41714174-G-T
• rs61753679
• NM_000037.4:c.1782C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000037.4(ANK1):​c.1782C>A​(p.Ser594Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,443,150 control chromosomes in the GnomAD database, including 955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (68 hom., cov: 32)
  • Exomes 𝑓: 0.034 (887 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.570
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-41714174-G-T is Benign according to our data. Variant chr8-41714174-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3482/152284) while in subpopulation NFE AF = 0.0361 (2454/68016). AF 95% confidence interval is 0.0349. There are 68 homozygotes in GnomAd4. There are 1587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 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.1782C>A	p.Ser594Ser	synonymous	Exon 16 of 43	NP_000028.3
	ANK1	NM_001142446.2		c.1881C>A	p.Ser627Ser	synonymous	Exon 16 of 43	NP_001135918.1	P16157-21
	ANK1	NM_020476.3		c.1782C>A	p.Ser594Ser	synonymous	Exon 16 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.1782C>A	p.Ser594Ser	synonymous	Exon 16 of 43	ENSP00000289734.8	P16157-3
	ANK1	ENST00000265709.14	TSL:1	c.1881C>A	p.Ser627Ser	synonymous	Exon 16 of 43	ENSP00000265709.8	P16157-21
	ANK1	ENST00000347528.8	TSL:1	c.1782C>A	p.Ser594Ser	synonymous	Exon 16 of 42	ENSP00000339620.4	P16157-1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3481 AN: 152168 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00675

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0221 AC: 3902 AN: 176364 AF XY: 0.0218

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.00979

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0337 AC: 43556 AN: 1290866 Hom.: 887 Cov.: 30 AF XY: 0.0330 AC XY: 20756 AN XY: 629494

African (AFR) AF: 0.00541 AC: 162 AN: 29956

American (AMR) AF: 0.0222 AC: 755 AN: 34040

Ashkenazi Jewish (ASJ) AF: 0.00956 AC: 188 AN: 19670

East Asian (EAS) AF: 0.000111 AC: 4 AN: 35958

South Asian (SAS) AF: 0.00508 AC: 278 AN: 54772

European-Finnish (FIN) AF: 0.0156 AC: 723 AN: 46250

Middle Eastern (MID) AF: 0.00378 AC: 18 AN: 4764

European-Non Finnish (NFE) AF: 0.0394 AC: 39897 AN: 1013428

Other (OTH) AF: 0.0294 AC: 1531 AN: 52028

GnomAD4 genome AF: 0.0229 AC: 3482 AN: 152284 Hom.: 68 Cov.: 32 AF XY: 0.0213 AC XY: 1587 AN XY: 74460

African (AFR) AF: 0.00676 AC: 281 AN: 41572

American (AMR) AF: 0.0303 AC: 464 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0361 AC: 2454 AN: 68016

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0252 Hom.: 28

Bravo AF: 0.0238

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spherocytosis type 1 (3)
-	-	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	-0.55
CADD	Benign	9.0
DANN	Benign	0.70
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=68/32	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: rs61753679; hg19: chr8-41571692; COSMIC: COSV55888891;