2-37367233-C-T

Variant names:

• chr2-37367233-C-T
• rs151306583
• NM_012413.4:c.548C>T

Variant summary

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

The NM_012413.4(QPCT):​c.548C>T​(p.Thr183Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T183S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: QPCT NM_012413.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002886
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458
• Publications: 1 publications found

Genes affected

QPCT (HGNC:9753): (glutaminyl-peptide cyclotransferase) This gene encodes human pituitary glutaminyl cyclase, which is responsible for the presence of pyroglutamyl residues in many neuroendocrine peptides. The amino acid sequence of this enzyme is 86% identical to that of bovine glutaminyl cyclase. [provided by RefSeq, Jul 2008]

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=0.052983046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012413.4. 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
	QPCT	NM_012413.4	MANE Select	c.548C>T	p.Thr183Ile	missense splice_region	Exon 4 of 7	NP_036545.1	Q16769-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QPCT	ENST00000338415.8	TSL:1 MANE Select	c.548C>T	p.Thr183Ile	missense splice_region	Exon 4 of 7	ENSP00000344829.3	Q16769-1
	QPCT	ENST00000952066.1		c.548C>T	p.Thr183Ile	missense splice_region	Exon 4 of 6	ENSP00000622125.1
	QPCT	ENST00000404976.5	TSL:2	c.401C>T	p.Thr134Ile	missense splice_region	Exon 3 of 6	ENSP00000385391.1	B5MCZ9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248050 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457952 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725286

African (AFR) AF: 0.0000302 AC: 1 AN: 33166

American (AMR) AF: 0.00 AC: 0 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110432

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.46
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.017
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.077	B
Vest4		0.14
MutPred		0.43		Loss of disorder (P = 0.0342)
MVP		0.13
MPC		0.029
ClinPred		0.090	T
GERP RS		3.2
Varity_R		0.10
gMVP		0.38
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0040
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: rs151306583; hg19: chr2-37594376;