ENST00000557510.5:c.442G>A

Variant names:

• chr14-74480701-C-T
• rs140130028
• ENST00000557510.5:c.442G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

The ENST00000557510.5(NPC2):​c.442G>A​(p.Val148Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,612,688 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (43 hom.)
• Consequence: NPC2 ENST00000557510.5 missense
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:5 O:1
• Conservation: PhyloP100: -0.0370

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.299
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00388 (590/152256) while in subpopulation NFE AF= 0.00706 (480/68028). AF 95% confidence interval is 0.00653. There are 3 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC2	NM_006432.5	c.441+1G>A		splice_donor_variant, intron_variant	Intron 4 of 4	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.442G>A	p.Val148Ile	missense_variant	Exon 4 of 4		NP_001350617.1
NPC2	NM_001375440.1	c.364-413G>A		intron_variant	Intron 3 of 3		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.441+1G>A		splice_donor_variant, intron_variant	Intron 4 of 4	1	NM_006432.5	ENSP00000451112.2

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00706

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00373 AC: 937 AN: 251468 Hom.: 2 AF XY: 0.00388 AC XY: 527 AN XY: 135910

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00657 AC: 9595 AN: 1460432 Hom.: 43 Cov.: 31 AF XY: 0.00642 AC XY: 4663 AN XY: 726648

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00277

Gnomad4 NFE exome AF: 0.00797

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00388 AC: 590 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74450

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00608 Hom.: 4

Bravo AF: 0.00379

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00363 AC: 441

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C2 Pathogenic:1 Uncertain:4 Benign:2 Other:1

Jul 24, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela

Significance: Pathogenic

Review Status: flagged submission

Collection Method: research

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BS2, PS3, PP3 -

Dec 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_006432.3(NPC2):c.441+1G>A is a canonical splice variant classified as a variant of uncertain significance in the context of Niemann-Pick disease type C2. c.441+1G>A has been observed in cases with relevant disease (PMID: 26981555, 30548430, Mikhaylova_2011_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 25764212, 27792009). c.441+1G>A has been observed in population frequency databases (gnomAD: NFE 0.63%). In summary, there is insufficient evidence to classify NM_006432.3(NPC2):c.441+1G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 18, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PVS1,PP5. -

not provided Uncertain:3 Benign:3

Jul 09, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24386122, 27792009, 23352160, 23773996, 25764212, 24767253, 29431110, 30548430, 29928259) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC2: PVS1:Moderate, BS1, BS2 -

Jan 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, PVS1_moderate -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NPC2 c.441+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two of two in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. In one study, analysis of the variant using independent cell lines revealed multiple splicing events, the most prominent of which resulted in the insertion of 16 bases, leading to the alteration of the terminal 4 amino acids and the addition of 86 additional amino acids to the protein (Wassif_2016). In a different study, RT-PCR analysis showed the variant resulted in the synthesis of three aberrant transcripts, two of which would lead to a shift in the reading frame and premature termination codon (Cupidi_2016). Despite the impact on splicing, it is unclear what impact this would have on protein function. The variant allele was found at a frequency of 0.0037 in 254898 control chromosomes, predominantly at a frequency of 0.0064 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), suggesting that the variant is a benign polymorphism. c.441+1G>A has been reported in the literature in individuals with various neurological and psychiatric symptoms, with liver storage disease and in patients with not fully described phenotypes, and in cases where the second allele was not found/reported (Bauer_2013, Fernandez-Marmiesse_2014, McKay_2014, Wassif_2016, Zech_2013, Cupidi_2016). The variant was also reported in individuals affected with Niemann-Pick Disease Type C in the homozygous state, including a family with two fetuses with cystic hygroma (Gheldof_2018, Ples_2018, Reunert_2016). These data do not provide unequivocal evidence for pathogenicity. The following publications have been ascertained in the context of this evaluation (PMID: 23773996, 24767253, 23352160, 25764212, 26981555, 24386122, 30548430, 27792009, 29928259). ClinVar contains an entry for this variant (Variation ID: 100734). Based on the evidence outlined above, the variant was classified as uncertain significance. -

NPC2-related disorder Uncertain:1

Aug 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPC2 c.441+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was detected in the heterozygous state in one patient with a possible Niemann-Pick disease Type C phenotype and with no other pathogenic or likely pathogenic variants (Bauer et al. 2013. PubMed ID: 23773996). Another study reported this variant in the heterozygous state in patients with two autosomal dominant disorders (Parkinson's disease and frontotemporal lobar degeneration), and also in one control individual (Zech et al. 2013. PubMed ID: 24386122). At PreventionGenetics, we previously detected this variant in the heterozygous state in several other patients with various Niemann-Pick phenotypes. However, this variant is reported in 0.65% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including three homozygotes, which might be too common to be a highly penetrant cause of disease. While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Niemann-Pick disease, type C1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.65
Eigen	Benign	0.056
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.054	N
M_CAP	Benign	0.0026	T
ClinPred		0.0072	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs140130028; hg19: chr14-74947404; COSMIC: COSV53143541; COSMIC: COSV53143541;