4-155214382-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000910.4(NPY2R):c.443G>A(p.Arg148Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,868 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NPY2R
NM_000910.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.99

Variant links:

Genes affected

NPY2R (HGNC:7957): (neuropeptide Y receptor Y2) Predicted to enable calcium channel regulator activity and neuropeptide Y receptor activity. Involved in cardiac left ventricle morphogenesis and outflow tract morphogenesis. Located in cilium. Implicated in Huntington's disease; morbid obesity; and obesity. Biomarker of peripheral artery disease and temporal lobe epilepsy. [provided by Alliance of Genome Resources, Apr 2022]

NPY2R links:

MAP9-AS1 (HGNC:56110): (MAP9 antisense RNA 1)

MAP9-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPY2R	NM_000910.4 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	2/2	ENST00000329476.4
NPY2R	NM_001370180.1 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	2/2
NPY2R	NM_001375470.1 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NPY2R	ENST00000329476.4 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	2/2	1	NM_000910.4	P1
NPY2R	ENST00000506608.1 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	2/2	1		P1
MAP9-AS1	ENST00000630664.2 linkuse as main transcript	n.208+40098G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

The c.443G>A (p.R148Q) alteration is located in exon 2 (coding exon 1) of the NPY2R gene. This alteration results from a G to A substitution at nucleotide position 443, causing the arginine (R) at amino acid position 148 to be replaced by a glutamine (Q). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.89

Loss of catalytic residue at R148 (P = 0.268);Loss of catalytic residue at R148 (P = 0.268);

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.81

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over