rs1555634643

Variant names:

• chr18-23544946-C-CA
• rs1555634643
• NM_000271.5:c.1947+13_1947+14insT

Your query was ambiguous. Multiple possible variants found:

• chr18-23544946-C-CA
• chr18-23544946-C-CG
• chr18-23544946-C-CT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000271.5(NPC1):​c.1947+13_1947+14insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,193,804 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000022 (1 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.996
• Publications: 0 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 -8 ACMG points.

• BP6: Variant 18-23544946-C-CA is Benign according to our data. Variant chr18-23544946-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 255692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1947+13_1947+14insT		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.1947+13_1947+14insT		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+13_1998+14insT		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+13_1947+14insT		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.0000729 AC: 17 AN: 233216 AF XY: 0.0000788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.0000218 AC: 26 AN: 1193804 Hom.: 1 Cov.: 25 AF XY: 0.0000265 AC XY: 16 AN XY: 602958

African (AFR) AF: 0.00 AC: 0 AN: 30282

American (AMR) AF: 0.000240 AC: 10 AN: 41612

Ashkenazi Jewish (ASJ) AF: 0.0000814 AC: 2 AN: 24582

East Asian (EAS) AF: 0.00 AC: 0 AN: 32172

South Asian (SAS) AF: 0.0000883 AC: 7 AN: 79238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.00000567 AC: 5 AN: 882400

Other (OTH) AF: 0.0000395 AC: 2 AN: 50684

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs1555634643; hg19: chr18-21124910;