12-47236325-G-A

Variant names:

• chr12-47236325-G-A
• rs374835427
• NM_138371.3:c.1262G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138371.3(PCED1B):​c.1262G>A​(p.Arg421Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCED1B NM_138371.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 0 publications found

Genes affected

PCED1B (HGNC:28255): (PC-esterase domain containing 1B) This gene encodes a protein that belongs to the GDSL/SGNH-like acyl-esterase family. Members of this family are hydrolases thought to function in modification of biopolymers on the cell surface. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05973935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCED1B	NM_138371.3	c.1262G>A	p.Arg421Lys	missense_variant	Exon 4 of 4	ENST00000546455.6	NP_612380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCED1B	ENST00000546455.6	c.1262G>A	p.Arg421Lys	missense_variant	Exon 4 of 4	1	NM_138371.3	ENSP00000446688.1
PCED1B	ENST00000432328.2	c.1262G>A	p.Arg421Lys	missense_variant	Exon 3 of 3	3		ENSP00000396040.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458716 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725596

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110590

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.33	.;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		0.28
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.085
Sift	Benign	0.22	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.096	B;B
Vest4		0.071
MutPred		0.28		Gain of catalytic residue at K420 (P = 5e-04);Gain of catalytic residue at K420 (P = 5e-04);
MVP		0.15
MPC		1.1
ClinPred		0.12	T
GERP RS		0.81
Varity_R		0.073
gMVP		0.19
Mutation Taster		=100/0	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

dbSNP: rs374835427; hg19: chr12-47630108; COSMIC: COSV71395100; COSMIC: COSV71395100;