chr8-41668396-C-T

Variant names:

• chr8-41668396-C-T
• rs750625
• NM_000037.4:c.5265G>A
• ANK1 p.Val1755Val

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB4_Strong

The NM_000037.4(ANK1):c.5265G>A (p.Val1755Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.234 (AC=377,206) in the gnomAD database across 1,614,112 control chromosomes, including 45,182 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.272. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 3 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: 𝑓 0.23 (4040 hom., cov: 33)
  • Exomes 𝑓: 0.23 (41142 hom.)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.27
• Publications: 28 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: AD, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• hereditary spherocytosis type 1

  Inheritance: SD, AR, AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.272 — exceeds 1% threshold (B1 applied)
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000037.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ANK1 NM_000037.4	MANE Select	c.5265G>A p.Val1755Val	synonymous	Exon 39 of 43	Prot: NP_000028.3
	ANK1 NM_001142446.2		c.5388G>A p.Val1796Val	synonymous	Exon 40 of 43	Prot: NP_001135918.1 UniProt:
	ANK1 NM_020476.3		c.5265G>A p.Val1755Val	synonymous	Exon 39 of 42	Prot: NP_065209.2 UniProt:

ANK1 NM_000037.4

MANE Select

HGVSc / HGVSpc.5265G>Ap.Val1755Val

Exon rankExon 39 of 43

synonymous

Prot: NP_000028.3

ANK1 NM_001142446.2

HGVSc / HGVSpc.5388G>Ap.Val1796Val

Exon rankExon 40 of 43

synonymous

Prot: NP_001135918.1UniProt: P16157-21

ANK1 NM_020476.3

HGVSc / HGVSpc.5265G>Ap.Val1755Val

Exon rankExon 39 of 42

synonymous

Prot: NP_065209.2UniProt: P16157-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ANK1 ENST00000289734.13	TSL:1MANE Select	c.5265G>A p.Val1755Val	synonymous	Exon 39 of 43	Prot: ENSP00000289734.8 UniProt:
	ANK1 ENST00000265709.14	TSL:1	c.5388G>A p.Val1796Val	synonymous	Exon 40 of 43	Prot: ENSP00000265709.8 UniProt:
	ANK1 ENST00000347528.8	TSL:1	c.5265G>A p.Val1755Val	synonymous	Exon 39 of 42	Prot: ENSP00000339620.4 UniProt:

ANK1 ENST00000289734.13

TSL:1MANE Select

HGVSc / HGVSpc.5265G>Ap.Val1755Val

Exon rankExon 39 of 43

synonymous

Prot: ENSP00000289734.8UniProt: P16157-3

ANK1 ENST00000265709.14

TSL:1

HGVSc / HGVSpc.5388G>Ap.Val1796Val

Exon rankExon 40 of 43

synonymous

Prot: ENSP00000265709.8UniProt: P16157-21

ANK1 ENST00000347528.8

TSL:1

HGVSc / HGVSpc.5265G>Ap.Val1755Val

Exon rankExon 39 of 42

synonymous

Prot: ENSP00000339620.4UniProt: P16157-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.227	AC:34461	Hom:4030	AN:152128	Cov:33
GnomAD2 exomes	AF: 0.217	AC:54591	Hom:	AN:251474	Cov:
GnomAD4 exome	AF: 0.234	AC:342714	Hom:41142	AN:1461866	Cov:37
GnomAD4 genome	AF: 0.227	AC:34492	Hom:4040	AN:152246	Cov:33
TOPMed (Bravo)	AF: 0.231	AC:61162	Hom:7337	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.236	AC:110733	Hom:13817	AN:468812	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.248	AC:580	Hom:73	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.120	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.233	AC:70	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.231	AC:3007	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.141	AC:490	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.115	AC:830	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.237	AC:477	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.139	AC:17021	Hom:1219	AN:122770	Cov:
Turkish Variome	AF: 0.297	AC:1999	Hom:325	AN:6720	Cov:
UK10K	AF: 0.247	AC:1867	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.133	AC:1195	Hom:80	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.219 *	2404	11002	0.210 *	3682	17524
BipEx(Bipolar disorder (including schizoaffective))	0.230	6536	28420	0.234	6738	28844
Epi25(Epilepsy)	0.236	9893	41958	0.239	15999	66888
SCHEMA(Schizophrenia)	0.247	33954	137270	0.264	59660	225620

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spherocytosis type 1 (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Spherocytosis (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.0
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.60
GPN-Star LLR	N/A	-1.5
GPN-Star score	N/A	1.5
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	1.3
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.2

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs750625;

hg19: chr8-41525914;

COSMIC: COSV55881841;

COSMIC: COSV55881841;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar