8-41672445-C-G

Position:

• chr8-41672445-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000289734.13(ANK1):​c.5005G>C​(p.Glu1669Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANK1 ENST00000289734.13 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK1. . Gene score misZ 2.0781 (greater than the threshold 3.09). Trascript score misZ 3.8314 (greater than threshold 3.09). GenCC has associacion of gene with hereditary spherocytosis type 1, hereditary spherocytosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23868772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK1	NM_000037.4	c.5005G>C	p.Glu1669Gln	missense_variant	38/43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13	c.5005G>C	p.Glu1669Gln	missense_variant	38/43	1	NM_000037.4	ENSP00000289734	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	0.59	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.076	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.82	P;P;P
Vest4		0.21
MutPred		0.28		Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);.;
MVP		0.40
MPC		0.31
ClinPred		0.83	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.15

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: rs137852829; hg19: chr8-41529963;