14-74480292-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006432.5(NPC2):c.442-4A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,074 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (100 hom.)
• Consequence: NPC2 NM_006432.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.17

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-74480292-T-G is Benign according to our data. Variant chr14-74480292-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 197788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74480292-T-G is described in Lovd as [Likely_benign]. Variant chr14-74480292-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00767 (1168/152286) while in subpopulation SAS AF= 0.0315 (152/4822). AF 95% confidence interval is 0.0274. There are 19 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.442-4A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000555619.6
NPC2	NM_001363688.1	c.*326A>C		3_prime_UTR_variant	4/4
NPC2	NM_001375440.1	c.364-4A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.442-4A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152168 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00621 AC: 1547 AN: 249162 Hom.: 43 AF XY: 0.00741 AC XY: 1000 AN XY: 134882

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00285 AC: 4158 AN: 1459788 Hom.: 100 Cov.: 30 AF XY: 0.00374 AC XY: 2719 AN XY: 726380

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0342

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.00337

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152286 Hom.: 19 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74464

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00220 Hom.: 0

Bravo AF: 0.00742

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Niemann-Pick disease, type C2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Niemann-Pick disease, type C1 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.5
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.17		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: rs114950106; hg19: chr14-74946995;