chr18-23544950-C-A

Position:

• chr18-23544950-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000269228.10(NPC1):​c.1947+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,415,988 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 27)
  • Exomes 𝑓: 0.000084 (2 hom.)
• Consequence: NPC1 ENST00000269228.10 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.104

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+10G>T		intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+10G>T		intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1025+10G>T		intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.1861+10G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 27 AN: 143688 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000693

Gnomad ASJ AF: 0.000595

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000695

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000948

Gnomad OTH AF: 0.000512

GnomAD3 exomes AF: 0.000119 AC: 29 AN: 244166 Hom.: 1 AF XY: 0.000106 AC XY: 14 AN XY: 132590

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000636

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 107 AN: 1272186 Hom.: 2 Cov.: 26 AF XY: 0.0000922 AC XY: 59 AN XY: 640108

Gnomad4 AFR exome AF: 0.000736

Gnomad4 AMR exome AF: 0.000163

Gnomad4 ASJ exome AF: 0.000120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000590

Gnomad4 OTH exome AF: 0.0000935

GnomAD4 genome AF: 0.000202 AC: 29 AN: 143802 Hom.: 1 Cov.: 27 AF XY: 0.000171 AC XY: 12 AN XY: 70360

Gnomad4 AFR AF: 0.000372

Gnomad4 AMR AF: 0.0000692

Gnomad4 ASJ AF: 0.000595

Gnomad4 EAS AF: 0.000204

Gnomad4 SAS AF: 0.000696

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000948

Gnomad4 OTH AF: 0.000507

Alfa AF: 0.0000366 Hom.: 17

Bravo AF: 0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2016	Variant summary: The NPC1 c.1947+10G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict the variant to impact normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 116580 control chromosomes. However, this variant falls into hyper variable region consisted of poly-G track and there are many alterations of this region reported in NON-PASS filter option in ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor was it evaluated for functional impact by in vivo/vitro studies. Due to the absence of clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Niemann-Pick disease, type C1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.97
DANN	Benign	0.39

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: rs71534236; hg19: chr18-21124914;