NPC2 p.Val148Ile

Variant names:

• chr14-74480288-C-T
• NM_006432.5:c.442G>A
• NPC2 p.Val148Ile

Your query was ambiguous. Multiple possible variants found:

• chr14-74480288-C-T
• chr14-74480286-AAC-GAT
• chr14-74480286-AAC-TAT

Variant summary

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

The NM_006432.5(NPC2):​c.442G>A​(p.Val148Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPC2 NM_006432.5 missense, splice_region
• Scores: Splicing: ADA: 0.008030
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635
• Publications: 0 publications found

Genes affected

NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

SYNDIG1L (HGNC:32388): (synapse differentiation inducing 1 like) Predicted to be located in Golgi apparatus. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

MIR4709 (HGNC:41690): (microRNA 4709) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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=0.086592466).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006432.5. 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
	NPC2	NM_006432.5	MANE Select	c.442G>A	p.Val148Ile	missense splice_region	Exon 5 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001375440.1		c.364G>A	p.Val122Ile	missense splice_region	Exon 4 of 4	NP_001362369.1	P61916-2
	NPC2	NM_001363688.1		c.*330G>A		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.442G>A	p.Val148Ile	missense splice_region	Exon 5 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000557510.5	TSL:1	c.*330G>A		3_prime_UTR	Exon 4 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000553490.5	TSL:2	c.458G>A	p.Gly153Asp	missense splice_region	Exon 5 of 5	ENSP00000451180.1	G3V3D1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726844

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111514

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.89
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.60	T
PhyloP100		0.64
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.12
Sift	Benign	0.039	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0080
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-74946991;