rs142700149

chr18-23560194-G-Cchr18-23560194-G-T

Variant summary

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

The NM_000271.5(NPC1):c.881+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,613,404 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.710

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-23560194-G-C is Benign according to our data. Variant chr18-23560194-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 255702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00311 (474/152316) while in subpopulation AFR AF= 0.0109 (455/41570). AF 95% confidence interval is 0.0101. There are 4 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.881+37C>G		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.881+37C>G		intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.112+37C>G		intron_variant		2
NPC1	ENST00000540608.5	n.795+37C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000816 AC: 204 AN: 250076 Hom.: 0 AF XY: 0.000657 AC XY: 89 AN XY: 135390

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000313 AC: 457 AN: 1461088 Hom.: 2 Cov.: 31 AF XY: 0.000288 AC XY: 209 AN XY: 726854

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74478

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.00333

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.6
Dann	Benign	0.63

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: rs142700149; hg19: chr18-21140158;