18-23544950-C-CCCCA

Variant names:

• chr18-23544950-C-CCCCA
• rs772150994
• NM_000271.5:c.1947+9_1947+10insTGGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000271.5(NPC1):​c.1947+9_1947+10insTGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,415,974 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000083 (1 hom., cov: 27)
  • Exomes 𝑓: 0.00011 (8 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.825
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 18-23544950-C-CCCCA is Benign according to our data. Variant chr18-23544950-C-CCCCA is described in ClinVar as Likely_benign. ClinVar VariationId is 2067713.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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+9_1947+10insTGGG		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+9_1947+10insTGGG		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+9_1998+10insTGGG		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+9_1947+10insTGGG		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.0000835 AC: 12 AN: 143688 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000158

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 136 AN: 1272172 Hom.: 8 Cov.: 26 AF XY: 0.000106 AC XY: 68 AN XY: 640100

African (AFR) AF: 0.0000320 AC: 1 AN: 31238

American (AMR) AF: 0.0000233 AC: 1 AN: 42970

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25068

East Asian (EAS) AF: 0.0000866 AC: 3 AN: 34644

South Asian (SAS) AF: 0.0000489 AC: 4 AN: 81850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.000123 AC: 117 AN: 948390

Other (OTH) AF: 0.000168 AC: 9 AN: 53488

GnomAD4 genome AF: 0.0000834 AC: 12 AN: 143802 Hom.: 1 Cov.: 27 AF XY: 0.0000569 AC XY: 4 AN XY: 70360

African (AFR) AF: 0.0000248 AC: 1 AN: 40346

American (AMR) AF: 0.00 AC: 0 AN: 14458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000158 AC: 10 AN: 63298

Other (OTH) AF: 0.00 AC: 0 AN: 1972

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Niemann-Pick disease, type C1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772150994; hg19: chr18-21124914;