8-98205206-C-A

Position:

• chr8-98205206-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001321635.2(NIPAL2):​c.696G>T​(p.Met232Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPAL2	NM_001321635.2	c.696G>T	p.Met232Ile	missense_variant	7/11	ENST00000430223.7	NP_001308564.1
NIPAL2-AS1	XR_928444.3	n.662+25162C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPAL2	ENST00000430223.7	c.696G>T	p.Met232Ile	missense_variant	7/11	1	NM_001321635.2	ENSP00000407087	P1
NIPAL2	ENST00000341166.3	c.696G>T	p.Met232Ile	missense_variant	7/12	2		ENSP00000339256
NIPAL2	ENST00000520545.5	n.715G>T		non_coding_transcript_exon_variant	6/10	2
NIPAL2	ENST00000521820.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 28, 2023

The c.696G>T (p.M232I) alteration is located in exon 7 (coding exon 7) of the NIPAL2 gene. This alteration results from a G to T substitution at nucleotide position 696, causing the methionine (M) at amino acid position 232 to be replaced by an isoleucine (I). 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	0.85
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		0.80	.;P
Vest4		0.88
MutPred		0.65		Loss of ubiquitination at K227 (P = 0.1191);Loss of ubiquitination at K227 (P = 0.1191);
MVP		0.61
MPC		0.46
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-99217434;