NM_001321635.2:c.124C>T

Variant names:

• chr8-98294014-G-A
• rs1026779970
• NM_001321635.2:c.124C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321635.2(NIPAL2):​c.124C>T​(p.Arg42Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,492,790 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. R42S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.233
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2385776).

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.124C>T	p.Arg42Cys	missense	Exon 1 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.124C>T	p.Arg42Cys	missense	Exon 1 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.124C>T	p.Arg42Cys	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.124C>T	p.Arg42Cys	missense	Exon 1 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.124C>T	p.Arg42Cys	missense	Exon 1 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.124C>T	p.Arg42Cys	missense	Exon 1 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000104 AC: 1 AN: 95810 AF XY: 0.0000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 12 AN: 1340630 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 9 AN XY: 660508

African (AFR) AF: 0.00 AC: 0 AN: 27010

American (AMR) AF: 0.00 AC: 0 AN: 28058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23574

East Asian (EAS) AF: 0.00 AC: 0 AN: 28658

South Asian (SAS) AF: 0.00 AC: 0 AN: 73660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.0000114 AC: 12 AN: 1052846

Other (OTH) AF: 0.00 AC: 0 AN: 55246

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.23
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.29
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.031	D
Polyphen		0.88	P
Vest4		0.15
MVP		0.55
MPC		0.50
ClinPred		0.95	D
GERP RS		-1.1
PromoterAI		-0.042	Neutral
Varity_R		0.12
gMVP		0.38
Mutation Taster		=93/7	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: rs1026779970; hg19: chr8-99306242;