14-74486315-C-T

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.190+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,571,414 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (41 hom.)
• Consequence: NPC2 NM_006432.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.15

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=-0.7).
• BP6: Variant 14-74486315-C-T is Benign according to our data. Variant chr14-74486315-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74486315-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00335 (510/152310) while in subpopulation SAS AF= 0.0116 (56/4824). AF 95% confidence interval is 0.00918. There are 2 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.190+14G>A		intron_variant		ENST00000555619.6
NPC2	NM_001363688.1	c.190+14G>A		intron_variant
NPC2	NM_001375440.1	c.190+14G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.190+14G>A		intron_variant		1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00476 AC: 923 AN: 193824 Hom.: 7 AF XY: 0.00556 AC XY: 570 AN XY: 102576

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000865

Gnomad ASJ exome AF: 0.00646

Gnomad EAS exome AF: 0.000133

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.00285

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00454 AC: 6441 AN: 1419104 Hom.: 41 Cov.: 30 AF XY: 0.00484 AC XY: 3402 AN XY: 702180

Gnomad4 AFR exome AF: 0.000364

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00290

Gnomad4 NFE exome AF: 0.00434

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00350 AC XY: 261 AN XY: 74486

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00519

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00371 Hom.: 0

Bravo AF: 0.00279

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Niemann-Pick disease, type C2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	-0.70
Cadd	Benign	4.1
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs189666920; hg19: chr14-74953018;