20-64106222-G-A

Position:

• chr20-64106222-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005286.4(NPBWR2):​c.610C>T​(p.Pro204Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPBWR2 NM_005286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

Genes affected

NPBWR2 (HGNC:4530): (neuropeptides B and W receptor 2) The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor. The encoded protein is similar in sequence to another G protein-coupled receptor (GPR7), and it is structurally similar to opioid and somatostatin receptors. This protein binds neuropeptides B and W. This gene is intronless and is expressed primarily in the frontal cortex of the brain. [provided by RefSeq, Jul 2008]

MYT1 (HGNC:7622): (myelin transcription factor 1) The protein encoded by this gene is a member of a family of neural specific, zinc finger-containing DNA-binding proteins. The protein binds to the promoter regions of proteolipid proteins of the central nervous system and plays a role in the developing nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPBWR2	NM_005286.4	c.610C>T	p.Pro204Ser	missense_variant	2/2	ENST00000684052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPBWR2	ENST00000684052.1	c.610C>T	p.Pro204Ser	missense_variant	2/2		NM_005286.4	P1
NPBWR2	ENST00000369768.1	c.610C>T	p.Pro204Ser	missense_variant	1/1			P1
MYT1	ENST00000644172.2	c.22+3667G>A		intron_variant
MYT1	ENST00000659024.1	c.-313+3667G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460422 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.610C>T (p.P204S) alteration is located in exon 1 (coding exon 1) of the NPBWR2 gene. This alteration results from a C to T substitution at nucleotide position 610, causing the proline (P) at amino acid position 204 to be replaced by a serine (S). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.65		Gain of loop (P = 0.1069);
MVP		0.84
MPC		0.89
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.82
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1980031262; hg19: chr20-62737575;