Genetic Variant NIPAL2:p.Met251Ile (chr8-98205149-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001321635.2(NIPAL2):c.753G>C(p.Met251Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 1 hom. )

Consequence

NIPAL2
NM_001321635.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

1 publications found

Variant links:

Genes affected

NIPAL2 (HGNC:25854): (NIPA like domain containing 2) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

NIPAL2 links:

NIPAL2-AS1 (HGNC:56271): (NIPAL2 antisense RNA 1)

NIPAL2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321635.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPAL2	NM_001321635.2	MANE Select	c.753G>C	p.Met251Ile	missense	Exon 7 of 11	NP_001308564.1	Q9H841-2
NIPAL2	NM_024759.3		c.753G>C	p.Met251Ile	missense	Exon 7 of 12	NP_079035.1	Q9H841-1
NIPAL2	NM_001321636.2		c.753G>C	p.Met251Ile	missense	Exon 7 of 10	NP_001308565.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPAL2	ENST00000430223.7	TSL:1 MANE Select	c.753G>C	p.Met251Ile	missense	Exon 7 of 11	ENSP00000407087.2	Q9H841-2
NIPAL2	ENST00000852806.1		c.753G>C	p.Met251Ile	missense	Exon 7 of 11	ENSP00000522865.1
NIPAL2	ENST00000341166.3	TSL:2	c.753G>C	p.Met251Ile	missense	Exon 7 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111796

Other (OTH)

AF:

0.00

AC:

AN:

60384

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.0

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.81

Sift

Uncertain

0.021

Sift4G

Uncertain

0.058

Polyphen

0.89

Vest4

0.80

MutPred

0.63

Loss of helix (P = 0.2271)

MVP

0.74

MPC

0.62

ClinPred

0.99

GERP RS

4.6

Varity_R

0.45

gMVP

0.77

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over