15-40281976-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001190479.3(ANKRD63):c.611C>G(p.Pro204Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000932 in 1,073,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: ANKRD63 NM_001190479.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

Genes affected

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

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]

ACMG classification

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=0.20235667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD63	NM_001190479.3	c.611C>G	p.Pro204Arg	missense_variant	1/1	ENST00000434396.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD63	ENST00000434396.2	c.611C>G	p.Pro204Arg	missense_variant	1/1		NM_001190479.3	P1
PLCB2	ENST00000560009.1	n.394+2463C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 9.32e-7 AC: 1 AN: 1073512 Hom.: 0 Cov.: 34 AF XY: 0.00000197 AC XY: 1 AN XY: 508248

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: 0.00000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

The c.611C>G (p.P204R) alteration is located in exon 1 (coding exon 1) of the ANKRD63 gene. This alteration results from a C to G substitution at nucleotide position 611, causing the proline (P) at amino acid position 204 to be replaced by an arginine (R). 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	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	0.97
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.90	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.062
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.64	T
Vest4		0.38
MutPred		0.32		Gain of MoRF binding (P = 0.0016);
MVP		0.31
ClinPred		0.49	T
GERP RS		3.3
Varity_R		0.24
gMVP		0.46

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: rs1337763089; hg19: chr15-40574177;