rs11694

Positions:

• chr14-74484579-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_006432.5(NPC2):​c.199T>C​(p.Ser67Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NPC2 NM_006432.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.25

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_pathogenic. Variant got 9 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 14-74484579-A-G is Pathogenic according to our data. Variant chr14-74484579-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 8482.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-74484579-A-G is described in Lovd as [Pathogenic]. Variant chr14-74484579-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC2	NM_006432.5	c.199T>C	p.Ser67Pro	missense_variant	3/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.199T>C	p.Ser67Pro	missense_variant	3/4		NP_001350617.1
NPC2	NM_001375440.1	c.199T>C	p.Ser67Pro	missense_variant	3/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.199T>C	p.Ser67Pro	missense_variant	3/5	1	NM_006432.5	ENSP00000451112	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Niemann-Pick disease, type C2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;D;.;.;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.5	.;M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.10	T;D;D;D;T;T;D
Sift4G	Uncertain	0.049	D;T;T;T;.;T;.
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.91
MutPred		0.81		Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);Loss of ubiquitination at K68 (P = 0.0533);
MVP		1.0
MPC		1.5
ClinPred		0.96	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.95

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

Other links and lift over

dbSNP: rs11694; hg19: chr14-74951282;