17-81902524-C-T

Variant names:

• chr17-81902524-C-T
• rs1007204540
• NM_148896.5:c.247C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_148896.5(NPB):​c.247C>T​(p.Leu83Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,303,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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. L83V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: NPB NM_148896.5 missense, splice_region
• Scores: Splicing: ADA: 0.03584
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06845915).

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.247C>T	p.Leu83Phe	missense splice_region	Exon 1 of 2	NP_683694.1	Q8NG41
	PCYT2	NM_002861.5	MANE Select	c.*2309G>A		3_prime_UTR	Exon 13 of 13	NP_002852.1	Q99447-1
	PCYT2	NM_001184917.3		c.*2309G>A		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.247C>T	p.Leu83Phe	missense splice_region	Exon 1 of 2	ENSP00000332766.7	Q8NG41
	PCYT2	ENST00000538936.7	TSL:1 MANE Select	c.*2309G>A		3_prime_UTR	Exon 13 of 13	ENSP00000439245.3	Q99447-1
	NPB	ENST00000573081.1	TSL:6	c.247C>T	p.Leu83Phe	missense	Exon 1 of 1	ENSP00000461824.1	I3NI19

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000230 AC: 3 AN: 1303682 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 639912

African (AFR) AF: 0.00 AC: 0 AN: 25370

American (AMR) AF: 0.00 AC: 0 AN: 21208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21656

East Asian (EAS) AF: 0.000102 AC: 3 AN: 29498

South Asian (SAS) AF: 0.00 AC: 0 AN: 70100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4900

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043232

Other (OTH) AF: 0.00 AC: 0 AN: 54204

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.082
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.051
Sift	Benign	0.038	D
Sift4G	Uncertain	0.034	D
Polyphen		0.0090	B
Vest4		0.056
MutPred		0.20		Loss of helix (P = 0.0626)
MVP		0.014
MPC		0.48
ClinPred		0.14	T
GERP RS		1.6
PromoterAI		-0.028	Neutral
Varity_R		0.074
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.036
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.010		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: rs1007204540; hg19: chr17-79860400;