Genetic Variant NPC2:c.190+14G>A (chr14-74486315-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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

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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics
Niemann-Pick disease type C, adult neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, juvenile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, late infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe early infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe perinatal form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 259982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.190+14G>A	intron	N/A	NP_006423.1	A0A024R6C0
NPC2	NM_001363688.1		c.190+14G>A	intron	N/A	NP_001350617.1	G3V3E8
NPC2	NM_001375440.1		c.190+14G>A	intron	N/A	NP_001362369.1	P61916-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPC2	ENST00000555619.6	TSL:1 MANE Select	c.190+14G>A	intron	N/A	ENSP00000451112.2	P61916-1
NPC2	ENST00000557510.5	TSL:1	c.190+14G>A	intron	N/A	ENSP00000451206.1	G3V3E8
NPC2	ENST00000553490.5	TSL:2	c.190+14G>A	intron	N/A	ENSP00000451180.1	G3V3D1

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

GnomAD2 exomes

AF:

0.00476

AC:

923

AN:

193824

AF XY:

0.00556

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 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

African (AFR)

AF:

0.000364

AC:

AN:

32980

American (AMR)

AF:

0.00107

AC:

AN:

38382

Ashkenazi Jewish (ASJ)

AF:

0.00597

AC:

151

AN:

25306

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38536

South Asian (SAS)

AF:

0.0134

AC:

1087

AN:

81054

European-Finnish (FIN)

AF:

0.00290

AC:

148

AN:

51100

Middle Eastern (MID)

AF:

0.00367

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00434

AC:

4716

AN:

1087198

Other (OTH)

AF:

0.00449

AC:

264

AN:

58820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

319

639

958

1278

1597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<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:

0.00335

AC:

510

AN:

152310

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

261

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41560

American (AMR)

AF:

0.000980

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0116

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00519

AC:

353

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00324

Hom.:

Bravo

AF:

0.00279

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Niemann-Pick disease, type C1 (1)

Niemann-Pick disease, type C2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.1

(source)

DANN

Benign

0.71

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism

(source)

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

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