17-81902399-C-G

Variant names:

• chr17-81902399-C-G
• rs1166421060
• NM_148896.5:c.122C>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.122C>G​(p.Ala41Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000588 in 1,191,330 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: NPB NM_148896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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=0.18839657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPB	NM_148896.5	c.122C>G	p.Ala41Gly	missense_variant	Exon 1 of 2	ENST00000333383.8	NP_683694.1
PCYT2	NM_002861.5	c.*2434G>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.122C>G	p.Ala41Gly	missense_variant	Exon 1 of 2	1	NM_148896.5	ENSP00000332766.7
PCYT2	ENST00000538936	c.*2434G>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_002861.5	ENSP00000439245.3
NPB	ENST00000573081.1	c.122C>G	p.Ala41Gly	missense_variant	Exon 1 of 1	6		ENSP00000461824.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000588 AC: 7 AN: 1191330 Hom.: 0 Cov.: 31 AF XY: 0.00000698 AC XY: 4 AN XY: 573184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000260

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122C>G (p.A41G) 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 122, causing the alanine (A) at amino acid position 41 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	.;N
REVEL	Benign	0.11
Sift	Uncertain	0.020	.;D
Sift4G	Uncertain	0.044	D;D
Polyphen		0.95	.;P
Vest4		0.16
MutPred		0.23		Loss of stability (P = 0.1201);Loss of stability (P = 0.1201);
MVP		0.040
MPC		0.84
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1166421060; hg19: chr17-79860275;