18-23544950-C-CCCCCT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000271.5(NPC1):​c.1947+9_1947+10insAGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000777 in 1,415,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000071 (0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-23544950-C-CCCCCT is Benign according to our data. Variant chr18-23544950-C-CCCCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 1138430.Status of the report is criteria_provided_single_submitter, 1 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+9_1947+10insAGGGG		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+10insAGGGG		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+9_1998+10insAGGGG		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+9_1947+10insAGGGG		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.0000139 AC: 2 AN: 143688 Hom.: 0 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000158

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000707 AC: 9 AN: 1272184 Hom.: 0 Cov.: 26 AF XY: 0.00000625 AC XY: 4 AN XY: 640104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31238

American (AMR) AF: 0.00 AC: 0 AN: 42970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34644

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81848

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: 0.00000633 AC: 6 AN: 948402

Other (OTH) AF: 0.0000187 AC: 1 AN: 53490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0267547), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000139 AC: 2 AN: 143688 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 70232

African (AFR) AF: 0.0000249 AC: 1 AN: 40224

American (AMR) AF: 0.00 AC: 0 AN: 14440

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4920

South Asian (SAS) AF: 0.00 AC: 0 AN: 4314

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000158 AC: 1 AN: 63304

Other (OTH) AF: 0.00 AC: 0 AN: 1954

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

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;