15-40282174-C-T

Variant names:

• chr15-40282174-C-T
• NM_001190479.3:c.413G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001190479.3(ANKRD63):​c.413G>A​(p.Arg138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,341,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 7.5e-7 (0 hom.)
• Consequence: ANKRD63 NM_001190479.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2900874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190479.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD63	NM_001190479.3	MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 1 of 1	NP_001177408.1	C9JTQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD63	ENST00000434396.2	TSL:6 MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 1 of 1	ENSP00000399547.1	C9JTQ0
	PLCB2	ENST00000560009.1	TSL:4	n.394+2265G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1341046 Hom.: 0 Cov.: 35 AF XY: 0.00000151 AC XY: 1 AN XY: 660960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27008

American (AMR) AF: 0.00 AC: 0 AN: 29464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23480

East Asian (EAS) AF: 0.00 AC: 0 AN: 30742

South Asian (SAS) AF: 0.00 AC: 0 AN: 74568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4652

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062284

Other (OTH) AF: 0.00 AC: 0 AN: 55874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.98	L
PhyloP100		3.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.094
Sift	Benign	0.078	T
Sift4G	Benign	0.59	T
Vest4		0.28
MutPred		0.33		Loss of MoRF binding (P = 0.0278)
MVP		0.33
ClinPred		0.85	D
GERP RS		3.5
Varity_R		0.15
gMVP		0.31
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

hg19: chr15-40574375;