rs151220873

Positions:

chr14-74486431-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_006432.5(NPC2):c.88G>A(p.Val30Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,588,322 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 15 hom. )

Consequence

NPC2
NM_006432.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:14

Conservation

PhyloP100: -1.97

Variant links:

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]

NPC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain NPC intracellular cholesterol transporter 2 (size 131) in uniprot entity NPC2_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_006432.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0055167973).

BP6

Variant 14-74486431-C-T is Benign according to our data. Variant chr14-74486431-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 183281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74486431-C-T is described in Lovd as [Pathogenic]. Variant chr14-74486431-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00133 (203/152276) while in subpopulation SAS AF= 0.00497 (24/4826). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NPC2	NM_006432.5 linkuse as main transcript	c.88G>A	p.Val30Met	missense_variant	2/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1 linkuse as main transcript	c.88G>A	p.Val30Met	missense_variant	2/4		NP_001350617.1
NPC2	NM_001375440.1 linkuse as main transcript	c.88G>A	p.Val30Met	missense_variant	2/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6 linkuse as main transcript	c.88G>A	p.Val30Met	missense_variant	2/5	1	NM_006432.5	ENSP00000451112	P4	P61916-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00213

AC:

442

AN:

207464

Hom.:

AF XY:

0.00247

AC XY:

273

AN XY:

110464

show subpopulations

Gnomad AFR exome

AF:

0.0000758

Gnomad AMR exome

AF:

0.000918

Gnomad ASJ exome

AF:

0.0194

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00456

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00454

GnomAD4 exome

AF:

0.00139

AC:

1999

AN:

1436046

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1126

AN XY:

711534

show subpopulations

Gnomad4 AFR exome

AF:

0.000481

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.0189

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00495

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000737

Gnomad4 OTH exome

AF:

0.00293

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152276

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00156

AC:

189

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NPC2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	This variant is associated with the following publications: (PMID: 32858489, 15465422, 30556376, 15937921, 12955717, 25764212, 24386122, 21228398, 27792009, 25558065, 27884173, 25099932) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2017	- -

Niemann-Pick disease, type C2

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2022	Variant summary: NPC2 c.88G>A (p.Val30Met) results in a conservative amino acid change located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 207464 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.88G>A with Niemann-Pick Disease Type C has been reported in the literature. A functional study examining the expression and localization of NPC2 missense variants in human fibroblasts found no biological abnormalities in cells expressing this variant, suggesting it does not strongly impact protein function (Chikh_2005). Seven assessments for this variant have been submitted to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -

Seizure;C0557874:Global developmental delay;C4551563:Microcephaly;C4551584:Brain atrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;T;.;.;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.77

T;T;T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0055

T;T;T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.3

.;L;L;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.34

N;N;N;N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.11

T;T;T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;.;T;.

Polyphen

0.92

.;.;P;.;.;.;.

Vest4

0.69

MVP

0.42

MPC

1.1

ClinPred

0.060

GERP RS

-7.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.41

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over