chr8-41668396-C-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_ModerateBP7

The NM_000037.4(ANK1):c.5265G>C (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 0.00000657 (AC=1) in the gnomAD database across 152,158 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000241. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ANK1 NM_000037.4 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000241 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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>C p.Val1755Val	synonymous	Exon 39 of 43	Prot: NP_000028.3
	ANK1 NM_001142446.2		c.5388G>C p.Val1796Val	synonymous	Exon 40 of 43	Prot: NP_001135918.1 UniProt:
	ANK1 NM_020476.3		c.5265G>C p.Val1755Val	synonymous	Exon 39 of 42	Prot: NP_065209.2 UniProt:

ANK1 NM_000037.4

MANE Select

HGVSc / HGVSpc.5265G>Cp.Val1755Val

Exon rankExon 39 of 43

synonymous

Prot: NP_000028.3

ANK1 NM_001142446.2

HGVSc / HGVSpc.5388G>Cp.Val1796Val

Exon rankExon 40 of 43

synonymous

Prot: NP_001135918.1UniProt: P16157-21

ANK1 NM_020476.3

HGVSc / HGVSpc.5265G>Cp.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>C p.Val1755Val	synonymous	Exon 39 of 43	Prot: ENSP00000289734.8 UniProt:
	ANK1 ENST00000265709.14	TSL:1	c.5388G>C p.Val1796Val	synonymous	Exon 40 of 43	Prot: ENSP00000265709.8 UniProt:
	ANK1 ENST00000347528.8	TSL:1	c.5265G>C p.Val1755Val	synonymous	Exon 39 of 42	Prot: ENSP00000339620.4 UniProt:

ANK1 ENST00000289734.13

TSL:1MANE Select

HGVSc / HGVSpc.5265G>Cp.Val1755Val

Exon rankExon 39 of 43

synonymous

Prot: ENSP00000289734.8UniProt: P16157-3

ANK1 ENST00000265709.14

TSL:1

HGVSc / HGVSpc.5388G>Cp.Val1796Val

Exon rankExon 40 of 43

synonymous

Prot: ENSP00000265709.8UniProt: P16157-21

ANK1 ENST00000347528.8

TSL:1

HGVSc / HGVSpc.5265G>Cp.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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152158	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:37
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152158	Cov:33
TOPMed (Bravo) Warning	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:13817	AN:468812	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000440	1	22732	0.00	0	29210

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.0
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.54
GPN-Star LLR	N/A	-4.0
GPN-Star score	N/A	4.0
PhyloP100	Benign	1.3
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.2

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar