chr8-98252564-C-T

Variant names:

• chr8-98252564-C-T
• rs144226575
• NM_001321635.2:c.275G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001321635.2(NIPAL2):​c.275G>A​(p.Gly92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119
• Publications: 3 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05325058).

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.275G>A	p.Gly92Asp	missense	Exon 3 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.275G>A	p.Gly92Asp	missense	Exon 3 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.275G>A	p.Gly92Asp	missense	Exon 3 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.275G>A	p.Gly92Asp	missense	Exon 3 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.275G>A	p.Gly92Asp	missense	Exon 3 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.275G>A	p.Gly92Asp	missense	Exon 3 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000505 AC: 127 AN: 251356 AF XY: 0.000530

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461730 Hom.: 0 Cov.: 30 AF XY: 0.000347 AC XY: 252 AN XY: 727150

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000380 AC: 17 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00298 AC: 78 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86184

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.000326 AC: 363 AN: 1111978

Other (OTH) AF: 0.000613 AC: 37 AN: 60390

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74450

African (AFR) AF: 0.0000963 AC: 4 AN: 41554

American (AMR) AF: 0.00157 AC: 24 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000548 Hom.: 1

Bravo AF: 0.000733

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000982

EpiControl AF: 0.00107

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	Uncertain	0.43
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.12
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.35	B
Vest4		0.63
MVP		0.33
MPC		0.37
ClinPred		0.0058	T
GERP RS		1.9
Varity_R		0.041
gMVP		0.70
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: rs144226575; hg19: chr8-99264792;