Genetic Variant NPC2:c.*295C>G (chr14-74479979-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006432.5(NPC2):c.*295C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,363,896 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0084 ( 15 hom., cov: 32)

Exomes 𝑓: 0.012 ( 92 hom. )

Consequence

NPC2
NM_006432.5 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.138

Publications

1 publications found

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:

SYNDIG1L (HGNC:32388): (synapse differentiation inducing 1 like) Predicted to be located in Golgi apparatus. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYNDIG1L links:

MIR4709 (HGNC:41690): (microRNA 4709) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 14-74479979-G-C is Benign according to our data. Variant chr14-74479979-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314235.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00842 (1281/152048) while in subpopulation NFE AF = 0.0135 (921/67990). AF 95% confidence interval is 0.0128. There are 15 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPC2	NM_006432.5	MANE Select	c.*295C>G	3_prime_UTR	Exon 5 of 5	NP_006423.1	A0A024R6C0
NPC2	NM_001363688.1		c.*639C>G	3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
NPC2	NM_001375440.1		c.*295C>G	3_prime_UTR	Exon 4 of 4	NP_001362369.1	P61916-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPC2	ENST00000555619.6	TSL:1 MANE Select	c.*295C>G	3_prime_UTR	Exon 5 of 5	ENSP00000451112.2	P61916-1
NPC2	ENST00000238633.6	TSL:3	c.*295C>G	3_prime_UTR	Exon 5 of 5	ENSP00000238633.2	J3KMY5
NPC2	ENST00000541064.5	TSL:2	c.*295C>G	3_prime_UTR	Exon 4 of 4	ENSP00000442488.1	P61916-2

Frequencies

GnomAD3 genomes

AF:

0.00844

AC:

1282

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.00622

GnomAD4 exome

AF:

0.0118

AC:

14300

AN:

1211848

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

6730

AN XY:

588528

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

26590

American (AMR)

AF:

0.00276

AC:

AN:

18138

Ashkenazi Jewish (ASJ)

AF:

0.00137

AC:

AN:

16780

East Asian (EAS)

AF:

0.00

AC:

AN:

26562

South Asian (SAS)

AF:

0.0000163

AC:

AN:

61462

European-Finnish (FIN)

AF:

0.0294

AC:

602

AN:

20502

Middle Eastern (MID)

AF:

0.000619

AC:

AN:

4850

European-Non Finnish (NFE)

AF:

0.0134

AC:

13240

AN:

988222

Other (OTH)

AF:

0.00722

AC:

352

AN:

48742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

607

1215

1822

2430

3037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

530

1060

1590

2120

2650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00842

AC:

1281

AN:

152048

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

617

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41462

American (AMR)

AF:

0.00216

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0224

AC:

237

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

921

AN:

67990

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00828

Hom.:

Bravo

AF:

0.00652

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.1

(source)

DANN

Benign

0.56

PhyloP100

-0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over