8-98294025-C-G

Variant names:

• chr8-98294025-C-G
• rs751345147
• NM_001321635.2:c.113G>C

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.113G>C​(p.Gly38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 1,496,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. G38D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• 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=0.15891287).

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.113G>C	p.Gly38Ala	missense	Exon 1 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.113G>C	p.Gly38Ala	missense	Exon 1 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.113G>C	p.Gly38Ala	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.113G>C	p.Gly38Ala	missense	Exon 1 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.113G>C	p.Gly38Ala	missense	Exon 1 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.113G>C	p.Gly38Ala	missense	Exon 1 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1344128 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 662436

African (AFR) AF: 0.00 AC: 0 AN: 27092

American (AMR) AF: 0.00 AC: 0 AN: 28554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23648

East Asian (EAS) AF: 0.00 AC: 0 AN: 28752

South Asian (SAS) AF: 0.00 AC: 0 AN: 74058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1054710

Other (OTH) AF: 0.00 AC: 0 AN: 55452

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 67994

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.33	T
Polyphen		0.36	B
Vest4		0.12
MutPred		0.41		Loss of glycosylation at S37 (P = 0.0539)
MVP		0.64
MPC		0.16
ClinPred		0.15	T
GERP RS		2.0
PromoterAI		0.077	Neutral
Varity_R		0.096
gMVP		0.23
Mutation Taster		=90/10	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: rs751345147; hg19: chr8-99306253;