18-23544950-C-CCCCG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000271.5(NPC1):​c.1947+9_1947+10insCGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,415,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000044 (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, 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 -2 ACMG points.

• BP6: Variant 18-23544950-C-CCCCG is Benign according to our data. Variant chr18-23544950-C-CCCCG is described in ClinVar as [Likely_benign]. Clinvar id is 752048.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+9_1947+10insCGGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+9_1947+10insCGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+9_1023+10insCGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+9_1861+10insCGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0000487 AC: 7 AN: 143688 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000474

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000440 AC: 56 AN: 1272162 Hom.: 0 Cov.: 26 AF XY: 0.0000453 AC XY: 29 AN XY: 640090

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

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

American (AMR) AF: 0.0000465 AC: 2 AN: 42968

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

East Asian (EAS) AF: 0.0000577 AC: 2 AN: 34646

South Asian (SAS) AF: 0.000183 AC: 15 AN: 81844

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49064

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

European-Non Finnish (NFE) AF: 0.0000359 AC: 34 AN: 948386

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000487 AC: 7 AN: 143802 Hom.: 0 Cov.: 27 AF XY: 0.0000569 AC XY: 4 AN XY: 70360

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

American (AMR) AF: 0.0000692 AC: 1 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: 0.000232 AC: 1 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: 0.0000474 AC: 3 AN: 63298

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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;