14-74480389-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000557510.5(NPC2):c.*229G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,043,482 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: NPC2 ENST00000557510.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.101

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-74480389-C-A is Benign according to our data. Variant chr14-74480389-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1213457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1551/152306) while in subpopulation AFR AF= 0.0357 (1482/41564). AF 95% confidence interval is 0.0341. There are 38 homozygotes in gnomad4. There are 731 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.442-101G>T		intron_variant		ENST00000555619.6
NPC2	NM_001363688.1	c.*229G>T		3_prime_UTR_variant	4/4
NPC2	NM_001375440.1	c.364-101G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.442-101G>T		intron_variant		1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1542 AN: 152188 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00115 AC: 1029 AN: 891176 Hom.: 15 Cov.: 13 AF XY: 0.000998 AC XY: 466 AN XY: 466904

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.0000444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000670

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.0102 AC: 1551 AN: 152306 Hom.: 38 Cov.: 32 AF XY: 0.00982 AC XY: 731 AN XY: 74474

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00230 Hom.: 2

Bravo AF: 0.0116

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	11
Dann	Benign	0.82

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: rs10220503; hg19: chr14-74947092;