chr17-81902312-T-C

Variant names:

• chr17-81902312-T-C
• rs1054263294
• NM_148896.5:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_148896.5(NPB):​c.35T>C​(p.Leu12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,182,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: NPB NM_148896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

NPB (HGNC:30099): (neuropeptide B) This gene encodes a member of the neuropeptide B/W family of proteins and preproprotein that is proteolytically processed to generate multiple protein products. The encoded products include neuropeptide B-23 and a C-terminally extended form, neuropeptide B-29, which are characterized by an N-terminal brominated tryptophan amino acid. Both of the encoded peptides bind with higher affinity to neuropeptide B/W (NPB/W) receptor 1 compared to the related NPB/W receptor 2. These peptides may regulate feeding, pain perception, and stress in rodents. [provided by RefSeq, Jul 2015]

PCYT2 (HGNC:8756): (phosphate cytidylyltransferase 2, ethanolamine) This gene encodes an enzyme that catalyzes the formation of CDP-ethanolamine from CTP and phosphoethanolamine in the Kennedy pathway of phospholipid synthesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

PCYT2 Gene-Disease associations (from GenCC):

• spastic paraplegia 82, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148896.5. 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
	NPB	NM_148896.5	MANE Select	c.35T>C	p.Leu12Pro	missense	Exon 1 of 2	NP_683694.1	Q8NG41
	PCYT2	NM_002861.5	MANE Select	c.*2521A>G		3_prime_UTR	Exon 13 of 13	NP_002852.1	Q99447-1
	PCYT2	NM_001184917.3		c.*2521A>G		3_prime_UTR	Exon 14 of 14	NP_001171846.1	Q99447-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPB	ENST00000333383.8	TSL:1 MANE Select	c.35T>C	p.Leu12Pro	missense	Exon 1 of 2	ENSP00000332766.7	Q8NG41
	PCYT2	ENST00000538936.7	TSL:1 MANE Select	c.*2521A>G		3_prime_UTR	Exon 13 of 13	ENSP00000439245.3	Q99447-1
	NPB	ENST00000573081.1	TSL:6	c.35T>C	p.Leu12Pro	missense	Exon 1 of 1	ENSP00000461824.1	I3NI19

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000254 AC: 3 AN: 1182344 Hom.: 0 Cov.: 31 AF XY: 0.00000174 AC XY: 1 AN XY: 573458

African (AFR) AF: 0.00 AC: 0 AN: 23566

American (AMR) AF: 0.0000897 AC: 1 AN: 11154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16578

East Asian (EAS) AF: 0.00 AC: 0 AN: 26904

South Asian (SAS) AF: 0.00 AC: 0 AN: 43786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3280

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 981532

Other (OTH) AF: 0.00 AC: 0 AN: 48192

GnomAD4 genome Cov.: 33

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	Benign	0.24
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.53		Gain of glycosylation at L12 (P = 0.0131)
MVP		0.055
MPC		1.1
ClinPred		0.98	D
GERP RS		3.5
PromoterAI		0.00050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.83
gMVP		0.48

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: rs1054263294; hg19: chr17-79860188;