chr14-74486315-C-T

Position:

chr14-74486315-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
NPC2	NM_006432.5 linkuse as main transcript	c.190+14G>A	intron_variant	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1 linkuse as main transcript	c.190+14G>A	intron_variant		NP_001350617.1
NPC2	NM_001375440.1 linkuse as main transcript	c.190+14G>A	intron_variant		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6 linkuse as main transcript	c.190+14G>A		intron_variant		1	NM_006432.5	ENSP00000451112.2		P61916-1

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

509

AN:

152192

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00556

AC XY:

570

AN XY:

102576

show subpopulations

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.:

Cov.:

AF XY:

0.00484

AC XY:

3402

AN XY:

702180

show subpopulations

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.:

Cov.:

AF XY:

0.00350

AC XY:

261

AN XY:

74486

show subpopulations

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.:

Bravo

AF:

0.00279

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over