chr8-98252606-T-C

Variant names:

• chr8-98252606-T-C
• NM_001321635.2:c.233A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001321635.2(NIPAL2):​c.233A>G​(p.Gln78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NIPAL2 NM_001321635.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.445
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0413391).

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.233A>G	p.Gln78Arg	missense	Exon 3 of 11	NP_001308564.1	Q9H841-2
	NIPAL2	NM_024759.3		c.233A>G	p.Gln78Arg	missense	Exon 3 of 12	NP_079035.1	Q9H841-1
	NIPAL2	NM_001321636.2		c.233A>G	p.Gln78Arg	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.233A>G	p.Gln78Arg	missense	Exon 3 of 11	ENSP00000407087.2	Q9H841-2
	NIPAL2	ENST00000852806.1		c.233A>G	p.Gln78Arg	missense	Exon 3 of 11	ENSP00000522865.1
	NIPAL2	ENST00000341166.3	TSL:2	c.233A>G	p.Gln78Arg	missense	Exon 3 of 12	ENSP00000339256.3	Q9H841-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460428 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726496

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111666

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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	0.061
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.35	N
PhyloP100		0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.096
Sift	Benign	0.48	T
Sift4G	Benign	0.59	T
Polyphen		0.0070	B
Vest4		0.098
MutPred		0.29		Gain of sheet (P = 0.0477)
MVP		0.32
MPC		0.16
ClinPred		0.087	T
GERP RS		3.3
Varity_R		0.067
gMVP		0.25
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

hg19: chr8-99264834;