8-98294038-C-T

Variant names:

• chr8-98294038-C-T
• rs754692013
• NM_001321635.2:c.100G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001321635.2(NIPAL2):​c.100G>A​(p.Gly34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

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]

LOC105375659 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3641048).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL2	NM_001321635.2	MANE Select	c.100G>A	p.Gly34Ser	missense	Exon 1 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.100G>A	p.Gly34Ser	missense	Exon 1 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.100G>A	p.Gly34Ser	missense	Exon 1 of 10	NP_001308565.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL2	ENST00000430223.7	TSL:1 MANE Select	c.100G>A	p.Gly34Ser	missense	Exon 1 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.100G>A	p.Gly34Ser	missense	Exon 1 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.100G>A	p.Gly34Ser	missense	Exon 1 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345114 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 662940

African (AFR) AF: 0.00 AC: 0 AN: 27116

American (AMR) AF: 0.00 AC: 0 AN: 28590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23704

East Asian (EAS) AF: 0.0000348 AC: 1 AN: 28738

South Asian (SAS) AF: 0.00 AC: 0 AN: 74186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4882

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055292

Other (OTH) AF: 0.00 AC: 0 AN: 55482

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.28
Sift	Benign	0.046	D
Sift4G	Benign	0.37	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.31		Gain of glycosylation at G34 (P = 0.0374)
MVP		0.70
MPC		0.51
ClinPred		0.95	D
GERP RS		4.5
PromoterAI		-0.026	Neutral
Varity_R		0.22
gMVP		0.39
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs754692013; hg19: chr8-99306266;