rs148171048

Variant names:

• chr8-98205217-C-T
• rs148171048
• NM_001321635.2:c.685G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001321635.2(NIPAL2):​c.685G>A​(p.Val229Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,612,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (1 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.416552).

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.685G>A	p.Val229Ile	missense	Exon 7 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.685G>A	p.Val229Ile	missense	Exon 7 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.685G>A	p.Val229Ile	missense	Exon 7 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.685G>A	p.Val229Ile	missense	Exon 7 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.685G>A	p.Val229Ile	missense	Exon 7 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.685G>A	p.Val229Ile	missense	Exon 7 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249918 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000719 AC: 105 AN: 1460724 Hom.: 1 Cov.: 30 AF XY: 0.0000784 AC XY: 57 AN XY: 726638

African (AFR) AF: 0.000149 AC: 5 AN: 33452

American (AMR) AF: 0.000112 AC: 5 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.000395 AC: 34 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111618

Other (OTH) AF: 0.0000663 AC: 4 AN: 60358

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74268

African (AFR) AF: 0.000145 AC: 6 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.60
Sift	Benign	0.10	T
Sift4G	Uncertain	0.020	D
Polyphen		0.96	P
Vest4		0.57
MVP		0.41
MPC		0.47
ClinPred		0.27	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.33
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148171048; hg19: chr8-99217445; COSMIC: COSV57838328; COSMIC: COSV57838328;