rs140130028

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BS1 BS2

The NM_006432.5(NPC2):​c.441+1G>A variant causes a splice donor, intron 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 benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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 NM_006432.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:5 O:1
• Conservation: PhyloP100: -0.0370
• Publications: 22 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]

NPC2 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17105263 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 16, new splice context is: gggGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 14-74480701-C-T is Benign according to our data. Variant chr14-74480701-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100734.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.441+1G>A		splice_donor intron	N/A	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.442G>A	p.Val148Ile	missense	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.364-413G>A		intron	N/A	NP_001362369.1	P61916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000557510.5	TSL:1	c.442G>A	p.Val148Ile	missense	Exon 4 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.441+1G>A		splice_donor intron	N/A	ENSP00000451112.2	P61916-1
	NPC2	ENST00000553490.5	TSL:2	c.442G>A	p.Val148Ile	missense	Exon 4 of 5	ENSP00000451180.1	G3V3D1

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

GnomAD2 exomes AF: 0.00373 AC: 937 AN: 251468 AF XY: 0.00388

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 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

African (AFR) AF: 0.000807 AC: 27 AN: 33460

American (AMR) AF: 0.00125 AC: 56 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00152 AC: 131 AN: 86230

European-Finnish (FIN) AF: 0.00277 AC: 148 AN: 53410

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00797 AC: 8854 AN: 1110674

Other (OTH) AF: 0.00573 AC: 346 AN: 60348

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

African (AFR) AF: 0.00132 AC: 55 AN: 41538

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00706 AC: 480 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00616 Hom.: 14

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	5	2	Niemann-Pick disease, type C2 (9)
-	3	3	not provided (6)
-	1	-	Niemann-Pick disease, type C1 (1)
-	1	-	not specified (1)
-	1	-	NPC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
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
PhyloP100		-0.037
ClinPred		0.0072	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=96/4	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.55
Splicevardb		3.0
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

Other links and lift over

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