17-81902515-C-A

Variant names:

• chr17-81902515-C-A
• rs533951965
• NM_148896.5:c.238C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_148896.5(NPB):​c.238C>A​(p.Leu80Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000812 in 1,446,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (0 hom.)
• Consequence: NPB NM_148896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.474

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016582638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPB	NM_148896.5	c.238C>A	p.Leu80Met	missense_variant	Exon 1 of 2	ENST00000333383.8	NP_683694.1
PCYT2	NM_002861.5	c.*2318G>T		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.238C>A	p.Leu80Met	missense_variant	Exon 1 of 2	1	NM_148896.5	ENSP00000332766.7
PCYT2	ENST00000538936	c.*2318G>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_002861.5	ENSP00000439245.3
NPB	ENST00000573081.1	c.238C>A	p.Leu80Met	missense_variant	Exon 1 of 1	6		ENSP00000461824.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000538 AC: 31 AN: 57628 Hom.: 0 AF XY: 0.000560 AC XY: 19 AN XY: 33952

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000600

GnomAD4 exome AF: 0.000847 AC: 1096 AN: 1294482 Hom.: 0 Cov.: 31 AF XY: 0.000794 AC XY: 504 AN XY: 634418

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000974

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000540

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74504

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000589

ExAC AF: 0.000116 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238C>A (p.L80M) alteration is located in exon 1 (coding exon 1) of the NPB gene. This alteration results from a C to A substitution at nucleotide position 238, causing the leucine (L) at amino acid position 80 to be replaced by a methionine (M). 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	0.20
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.31	T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.071
Sift	Benign	0.050	.;D
Sift4G	Benign	0.064	T;D
Polyphen		0.96	.;D
Vest4		0.19
MVP		0.014
MPC		0.84
ClinPred		0.10	T
GERP RS		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Varity_R		0.084
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs533951965; hg19: chr17-79860391;