17-81902524-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_148896.5(NPB):​c.247C>G​(p.Leu83Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPB NM_148896.5 missense, splice_region
• Scores: Splicing: ADA: 0.002702
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07836771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPB	NM_148896.5	c.247C>G	p.Leu83Val	missense_variant, splice_region_variant	Exon 1 of 2	ENST00000333383.8	NP_683694.1
PCYT2	NM_002861.5	c.*2309G>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000538936.7	NP_002852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPB	ENST00000333383.8	c.247C>G	p.Leu83Val	missense_variant, splice_region_variant	Exon 1 of 2	1	NM_148896.5	ENSP00000332766.7
PCYT2	ENST00000538936	c.*2309G>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_002861.5	ENSP00000439245.3
NPB	ENST00000573081.1	c.247C>G	p.Leu83Val	missense_variant	Exon 1 of 1	6		ENSP00000461824.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247C>G (p.L83V) alteration is located in exon 1 (coding exon 1) of the NPB gene. This alteration results from a C to G substitution at nucleotide position 247, causing the leucine (L) at amino acid position 83 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.25	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	.;N
REVEL	Benign	0.034
Sift	Benign	0.056	.;T
Sift4G	Benign	0.082	T;T
Polyphen		0.56	.;P
Vest4		0.060
MutPred		0.19		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.014
MPC		0.79
ClinPred		0.30	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.063
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1007204540; hg19: chr17-79860400;