14-74479979-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.138

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]

SYNDIG1L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 314235.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.*295C>G		3_prime_UTR_variant	5/5	ENST00000555619.6
SYNDIG1L	XM_017021600.2	c.-5733C>G		5_prime_UTR_variant	1/4
NPC2	NM_001363688.1	c.*639C>G		3_prime_UTR_variant	4/4
NPC2	NM_001375440.1	c.*295C>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.*295C>G		3_prime_UTR_variant	5/5	1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 1282 AN: 151930 Hom.: 15 Cov.: 32

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.: 92 Cov.: 30 AF XY: 0.0114 AC XY: 6730 AN XY: 588528

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000163

Gnomad4 FIN exome AF: 0.0294

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.00842 AC: 1281 AN: 152048 Hom.: 15 Cov.: 32 AF XY: 0.00830 AC XY: 617 AN XY: 74342

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00828 Hom.: 1

Bravo AF: 0.00652

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

NPC2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.1
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113587712; hg19: chr14-74946682;