18-23544952-C-CCCCCG

Variant names:

• chr18-23544952-C-CCCCCG
• rs1555634618
• NM_000271.5:c.1947+7_1947+8insCGGGG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000271.5(NPC1):​c.1947+7_1947+8insCGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,427,790 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (16 hom., cov: 0)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0320
• 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, 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 18-23544952-C-CCCCCG is Benign according to our data. Variant chr18-23544952-C-CCCCCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 539314.
• BS2: High Homozygotes in GnomAd4 at 16 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.1947+7_1947+8insCGGGG		splice_region 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.1947+7_1947+8insCGGGG		splice_region intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.1023+7_1023+8insCGGGG		splice_region intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.1861+7_1861+8insCGGGG		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 569 AN: 143428 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.000489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00493

Gnomad OTH AF: 0.00362

GnomAD2 exomes AF: 0.000673 AC: 162 AN: 240878 AF XY: 0.000495

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000850

GnomAD4 exome AF: 0.000457 AC: 587 AN: 1284254 Hom.: 0 Cov.: 25 AF XY: 0.000452 AC XY: 292 AN XY: 645638

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

African (AFR) AF: 0.000127 AC: 4 AN: 31424

American (AMR) AF: 0.00400 AC: 165 AN: 41298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25152

East Asian (EAS) AF: 0.0000285 AC: 1 AN: 35134

South Asian (SAS) AF: 0.000401 AC: 33 AN: 82334

European-Finnish (FIN) AF: 0.000101 AC: 5 AN: 49508

Middle Eastern (MID) AF: 0.000367 AC: 2 AN: 5448

European-Non Finnish (NFE) AF: 0.000367 AC: 352 AN: 960114

Other (OTH) AF: 0.000464 AC: 25 AN: 53842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00397 AC: 570 AN: 143536 Hom.: 16 Cov.: 0 AF XY: 0.00375 AC XY: 263 AN XY: 70196

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

African (AFR) AF: 0.00121 AC: 49 AN: 40358

American (AMR) AF: 0.0137 AC: 188 AN: 13728

Ashkenazi Jewish (ASJ) AF: 0.000295 AC: 1 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 4930

South Asian (SAS) AF: 0.00184 AC: 8 AN: 4354

European-Finnish (FIN) AF: 0.000489 AC: 5 AN: 10218

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

European-Non Finnish (NFE) AF: 0.00492 AC: 312 AN: 63456

Other (OTH) AF: 0.00358 AC: 7 AN: 1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00113 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.032
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: rs1555634618; hg19: chr18-21124916;