rs151220873

Variant names:

• chr14-74486431-C-T
• rs151220873
• NM_006432.5:c.88G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/22 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:15
• Conservation: PhyloP100: -1.97
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 183281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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.88G>A	p.Val30Met	missense	Exon 2 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.88G>A	p.Val30Met	missense	Exon 2 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.88G>A	p.Val30Met	missense	Exon 2 of 4	NP_001362369.1	P61916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.88G>A	p.Val30Met	missense	Exon 2 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000557510.5	TSL:1	c.88G>A	p.Val30Met	missense	Exon 2 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000553490.5	TSL:2	c.88G>A	p.Val30Met	missense	Exon 2 of 5	ENSP00000451180.1	G3V3D1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152158 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00213 AC: 442 AN: 207464 AF XY: 0.00247

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 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.: 15 Cov.: 31 AF XY: 0.00158 AC XY: 1126 AN XY: 711534

African (AFR) AF: 0.000481 AC: 16 AN: 33266

American (AMR) AF: 0.000984 AC: 40 AN: 40658

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 482 AN: 25500

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.00495 AC: 407 AN: 82274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51960

Middle Eastern (MID) AF: 0.0124 AC: 71 AN: 5738

European-Non Finnish (NFE) AF: 0.000737 AC: 809 AN: 1097992

Other (OTH) AF: 0.00293 AC: 174 AN: 59442

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74450

African (AFR) AF: 0.000265 AC: 11 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00188 Hom.: 4

Bravo AF: 0.00134

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	5	Niemann-Pick disease, type C2 (5)
-	-	2	not specified (2)
1	-	-	Seizure;C0557874:Global developmental delay;C4551563:Microcephaly;C4551584:Brain atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
PhyloP100		-2.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.49
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.92	P
Vest4		0.69
MVP		0.42
MPC		1.1
ClinPred		0.060	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.41
Mutation Taster		=98/2	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

dbSNP: rs151220873; hg19: chr14-74953134; COSMIC: COSV99467354; COSMIC: COSV99467354;