Genetic Variant ANKRD63:p.Arg273Gln (chr15-40281769-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001190479.3(ANKRD63):c.818G>A(p.Arg273Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ANKRD63
NM_001190479.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

Variant links:

Genes affected

ANKRD63 (HGNC:40027): (ankyrin repeat domain 63)

ANKRD63 links:

PLCB2 (HGNC:9055): (phospholipase C beta 2) The protein encoded by this gene is a phosphodiesterase that catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. The encoded protein is activated by G proteins and has been shown to be involved in the type 2 taste receptor signal transduction pathway. In addition, nuclear factor kappa B can regulate the transcription of this gene, whose protein product is also an important regulator of platelet responses. [provided by RefSeq, Jan 2017]

PLCB2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19348362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD63	NM_001190479.3 link	c.818G>A	p.Arg273Gln	missense_variant	Exon 1 of 1	ENST00000434396.2	NP_001177408.1	C9JTQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD63	ENST00000434396.2 link	c.818G>A	p.Arg273Gln	missense_variant	Exon 1 of 1	6	NM_001190479.3	ENSP00000399547.1		C9JTQ0
PLCB2	ENST00000560009.1 link	n.394+2670G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1382754

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

682306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.818G>A (p.R273Q) alteration is located in exon 1 (coding exon 1) of the ANKRD63 gene. This alteration results from a G to A substitution at nucleotide position 818, causing the arginine (R) at amino acid position 273 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0071

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.48

REVEL

Benign

0.078

Sift

Uncertain

0.0020

Sift4G

Benign

0.51

Vest4

0.29

MutPred

0.53

Loss of MoRF binding (P = 0.0729);

MVP

0.21

ClinPred

0.72

GERP RS

3.5

Varity_R

0.12

gMVP

0.35

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over