17-81902411-C-G

Variant names:

• chr17-81902411-C-G
• rs926909028
• NM_148896.5:c.134C>G

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.134C>G​(p.Ser45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,347,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: NPB NM_148896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• 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=0.26067236).

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.134C>G	p.Ser45Cys	missense	Exon 1 of 2	NP_683694.1	Q8NG41
	PCYT2	NM_002861.5	MANE Select	c.*2422G>C		3_prime_UTR	Exon 13 of 13	NP_002852.1	Q99447-1
	PCYT2	NM_001184917.3		c.*2422G>C		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.134C>G	p.Ser45Cys	missense	Exon 1 of 2	ENSP00000332766.7	Q8NG41
	PCYT2	ENST00000538936.7	TSL:1 MANE Select	c.*2422G>C		3_prime_UTR	Exon 13 of 13	ENSP00000439245.3	Q99447-1
	NPB	ENST00000573081.1	TSL:6	c.134C>G	p.Ser45Cys	missense	Exon 1 of 1	ENSP00000461824.1	I3NI19

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1195620 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 575510

African (AFR) AF: 0.00 AC: 0 AN: 23408

American (AMR) AF: 0.00 AC: 0 AN: 9018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16674

East Asian (EAS) AF: 0.00 AC: 0 AN: 27020

South Asian (SAS) AF: 0.00 AC: 0 AN: 48682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3356

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 989026

Other (OTH) AF: 0.00 AC: 0 AN: 49400

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74306

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000483 AC: 2 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.054	T
Polyphen		0.97	D
Vest4		0.21
MutPred		0.31		Loss of glycosylation at S45 (P = 0.0046)
MVP		0.014
MPC		0.88
ClinPred		0.97	D
GERP RS		-0.44
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.33
gMVP		0.35
Mutation Taster		=74/26	polymorphism

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: rs926909028; hg19: chr17-79860287;