rs2435307

Variant names:

• chr18-23547946-C-T
• rs2435307
• NM_000271.5:c.1757+60G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000269228.10(NPC1):​c.1757+60G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 992,996 control chromosomes in the GnomAD database, including 117,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17050 hom., cov: 32)
  • Exomes 𝑓: 0.48 (100140 hom.)
• Consequence: NPC1 ENST00000269228.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103
• Publications: 22 publications found

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]

NPC1 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-23547946-C-T is Benign according to our data. Variant chr18-23547946-C-T is described in ClinVar as Benign. ClinVar VariationId is 1172933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000269228.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.1757+60G>A		intron	N/A	NP_000262.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.1757+60G>A		intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.834-2797G>A		intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.1671+60G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71332 AN: 151844 Hom.: 17030 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.483 AC: 406467 AN: 841034 Hom.: 100140 AF XY: 0.479 AC XY: 212892 AN XY: 443990

African (AFR) AF: 0.416 AC: 8946 AN: 21520

American (AMR) AF: 0.644 AC: 28299 AN: 43942

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 6623 AN: 22264

East Asian (EAS) AF: 0.634 AC: 23376 AN: 36876

South Asian (SAS) AF: 0.478 AC: 35321 AN: 73870

European-Finnish (FIN) AF: 0.496 AC: 26249 AN: 52894

Middle Eastern (MID) AF: 0.325 AC: 1480 AN: 4556

European-Non Finnish (NFE) AF: 0.473 AC: 257745 AN: 545016

Other (OTH) AF: 0.460 AC: 18428 AN: 40096

GnomAD4 genome AF: 0.470 AC: 71416 AN: 151962 Hom.: 17050 Cov.: 32 AF XY: 0.473 AC XY: 35171 AN XY: 74284

African (AFR) AF: 0.418 AC: 17312 AN: 41442

American (AMR) AF: 0.567 AC: 8661 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3468

East Asian (EAS) AF: 0.601 AC: 3106 AN: 5164

South Asian (SAS) AF: 0.470 AC: 2259 AN: 4810

European-Finnish (FIN) AF: 0.519 AC: 5477 AN: 10550

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.473 AC: 32147 AN: 67938

Other (OTH) AF: 0.442 AC: 930 AN: 2106

Alfa AF: 0.467 Hom.: 22287

Bravo AF: 0.476

Asia WGS AF: 0.541 AC: 1880 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Niemann-Pick disease, type C1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.36
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2435307; hg19: chr18-21127910; COSMIC: COSV52577265; COSMIC: COSV52577265;