rs2510344

Variant names:

• chr18-23533321-T-C
• rs2510344
• NM_000271.5:c.3754+34A>G

Variant summary

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

The NM_000271.5(NPC1):​c.3754+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,594,024 control chromosomes in the GnomAD database, including 195,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18597 hom., cov: 33)
  • Exomes 𝑓: 0.49 (176802 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.654
• Publications: 27 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
• 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=-0.82).
• BP6: Variant 18-23533321-T-C is Benign according to our data. Variant chr18-23533321-T-C is described in ClinVar as Benign. ClinVar VariationId is 255700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.3754+34A>G		intron	N/A	NP_000262.2	O15118-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.3754+34A>G		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000593280.2	TSL:1	c.85+34A>G		intron	N/A	ENSP00000467150.1	K7ENZ0
	NPC1	ENST00000897526.1		c.3805+34A>G		intron	N/A	ENSP00000567585.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74718 AN: 151976 Hom.: 18576 Cov.: 33

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.508 AC: 127350 AN: 250732 AF XY: 0.500

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.492 AC: 708936 AN: 1441930 Hom.: 176802 Cov.: 27 AF XY: 0.489 AC XY: 351693 AN XY: 718592

African (AFR) AF: 0.471 AC: 15593 AN: 33078

American (AMR) AF: 0.650 AC: 29074 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7867 AN: 25992

East Asian (EAS) AF: 0.657 AC: 26001 AN: 39600

South Asian (SAS) AF: 0.502 AC: 43104 AN: 85830

European-Finnish (FIN) AF: 0.498 AC: 26574 AN: 53370

Middle Eastern (MID) AF: 0.355 AC: 2030 AN: 5724

European-Non Finnish (NFE) AF: 0.485 AC: 530327 AN: 1093910

Other (OTH) AF: 0.475 AC: 28366 AN: 59728

GnomAD4 genome AF: 0.492 AC: 74800 AN: 152094 Hom.: 18597 Cov.: 33 AF XY: 0.495 AC XY: 36825 AN XY: 74340

African (AFR) AF: 0.475 AC: 19702 AN: 41486

American (AMR) AF: 0.582 AC: 8898 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3468

East Asian (EAS) AF: 0.624 AC: 3228 AN: 5172

South Asian (SAS) AF: 0.499 AC: 2404 AN: 4818

European-Finnish (FIN) AF: 0.520 AC: 5490 AN: 10566

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32546 AN: 67982

Other (OTH) AF: 0.465 AC: 982 AN: 2110

Alfa AF: 0.477 Hom.: 48199

Bravo AF: 0.499

Asia WGS AF: 0.564 AC: 1961 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		-0.65
PromoterAI		0.0096	Neutral
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: rs2510344; hg19: chr18-21113285; COSMIC: COSV52572089; COSMIC: COSV52572089;