chr17-81902300-C-T

Variant names:

• chr17-81902300-C-T
• NM_148896.5:c.23C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_148896.5(NPB):​c.23C>T​(p.Ala8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000854 in 1,171,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: NPB NM_148896.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.102
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030816466).
• BP6: Variant 17-81902300-C-T is Benign according to our data. Variant chr17-81902300-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3880674.Status of the report is criteria_provided_single_submitter, 1 stars.

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.23C>T	p.Ala8Val	missense	Exon 1 of 2	NP_683694.1	Q8NG41
	PCYT2	NM_002861.5	MANE Select	c.*2533G>A		3_prime_UTR	Exon 13 of 13	NP_002852.1	Q99447-1
	PCYT2	NM_001184917.3		c.*2533G>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.23C>T	p.Ala8Val	missense	Exon 1 of 2	ENSP00000332766.7	Q8NG41
	PCYT2	ENST00000538936.7	TSL:1 MANE Select	c.*2533G>A		3_prime_UTR	Exon 13 of 13	ENSP00000439245.3	Q99447-1
	NPB	ENST00000573081.1	TSL:6	c.23C>T	p.Ala8Val	missense	Exon 1 of 1	ENSP00000461824.1	I3NI19

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.54e-7 AC: 1 AN: 1171178 Hom.: 0 Cov.: 31 AF XY: 0.00000176 AC XY: 1 AN XY: 567280

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

African (AFR) AF: 0.00 AC: 0 AN: 23386

American (AMR) AF: 0.00 AC: 0 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16142

East Asian (EAS) AF: 0.00 AC: 0 AN: 26640

South Asian (SAS) AF: 0.0000241 AC: 1 AN: 41494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 975622

Other (OTH) AF: 0.00 AC: 0 AN: 47558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.69
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.27	N
PhyloP100		0.10
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.0060
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.13
MutPred		0.25		Loss of helix (P = 0.0376)
MVP		0.014
MPC		0.25
ClinPred		0.068	T
GERP RS		-0.53
PromoterAI		-0.059	Neutral
Varity_R		0.032
gMVP		0.32

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

hg19: chr17-79860176;