Variant 8-98203195-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001321635.2(NIPAL2):c.793T>C(p.Phe265Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NIPAL2
NM_001321635.2 missense, splice_region

Scores

Splicing: ADA: 0.009188

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL2	NM_001321635.2 link	c.793T>C	p.Phe265Leu	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000430223.7	NP_001308564.1	Q9H841-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPAL2	ENST00000430223.7 link	c.793T>C	p.Phe265Leu	missense_variant, splice_region_variant	Exon 8 of 11	1	NM_001321635.2	ENSP00000407087.2	Q9H841-2
NIPAL2	ENST00000341166.3 link	c.793T>C	p.Phe265Leu	missense_variant, splice_region_variant	Exon 8 of 12	2		ENSP00000339256.3	Q9H841-1
NIPAL2	ENST00000520545.5 link	n.812T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 10	2
NIPAL2	ENST00000521820.1 link	n.68T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.793T>C (p.F265L) alteration is located in exon 8 (coding exon 8) of the NIPAL2 gene. This alteration results from a T to C substitution at nucleotide position 793, causing the phenylalanine (F) at amino acid position 265 to be replaced by a leucine (L). 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

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;D

Eigen

Benign

-0.035

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.51

Sift

Benign

0.16

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.025

.;B

Vest4

0.37

MutPred

0.78

Loss of methylation at K264 (P = 0.0822);Loss of methylation at K264 (P = 0.0822);

MVP

0.65

MPC

0.19

ClinPred

0.95

GERP RS

4.2

Varity_R

0.38

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0092

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.45

Position offset: 1

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