Genetic Variant NIPA2:p.Lys33Lys (chr15-22851830-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PP3_ModerateBP6_Very_StrongBP7BA1

The NM_030922.7(NIPA2):c.99G>A(p.Lys33Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,609,850 control chromosomes in the GnomAD database, including 29,321 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3450 hom., cov: 31)

Exomes 𝑓: 0.18 ( 25871 hom. )

Consequence

NIPA2
NM_030922.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.595

Variant links:

Genes affected

NIPA2 (HGNC:17044): (NIPA magnesium transporter 2) This gene encodes a possible magnesium transporter. This gene is located adjacent to the imprinted domain in the Prader-Willi syndrome deletion region of chromosome 15. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 7 and 21.[provided by RefSeq, May 2010]

NIPA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

BayesDel_noAF computational evidence supports a deleterious effect, 0.31

BP6

Variant 15-22851830-G-A is Benign according to our data. Variant chr15-22851830-G-A is described in ClinVar as [Benign]. Clinvar id is 1221596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.595 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA2	NM_030922.7 link	c.99G>A	p.Lys33Lys	synonymous_variant	Exon 4 of 8	ENST00000337451.8	NP_112184.4	Q8N8Q9-1A0A024R372

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA2	ENST00000337451.8 link	c.99G>A	p.Lys33Lys	synonymous_variant	Exon 4 of 8	5	NM_030922.7	ENSP00000337618.3		Q8N8Q9-1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31192

AN:

151644

Hom.:

3442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.216

GnomAD3 exomes

AF:

0.215

AC:

53577

AN:

249672

Hom.:

6574

AF XY:

0.208

AC XY:

28027

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.382

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.237

Gnomad SAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.181

AC:

264482

AN:

1458086

Hom.:

25871

Cov.:

AF XY:

0.181

AC XY:

131596

AN XY:

725452

show subpopulations

Gnomad4 AFR exome

AF:

0.233

Gnomad4 AMR exome

AF:

0.372

Gnomad4 ASJ exome

AF:

0.221

Gnomad4 EAS exome

AF:

0.218

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.192

GnomAD4 genome

AF:

0.206

AC:

31230

AN:

151764

Hom.:

3450

Cov.:

AF XY:

0.207

AC XY:

15388

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.229

Gnomad4 AMR

AF:

0.308

Gnomad4 ASJ

AF:

0.225

Gnomad4 EAS

AF:

0.252

Gnomad4 SAS

AF:

0.195

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.173

Gnomad4 OTH

AF:

0.215

Alfa

AF:

0.175

Hom.:

3710

Bravo

AF:

0.217

Asia WGS

AF:

0.223

AC:

776

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NIPA2-related disorder

Benign:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

6.7

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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