NM_000271.5:c.1947+16dupG

Variant names:

• chr18-23544943-A-AC
• rs3837910
• NM_000271.5:c.1947+16dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.1947+16dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5470 hom., cov: 0)
  • Exomes 𝑓: 0.17 (6285 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.952
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 18-23544943-A-AC is Benign according to our data. Variant chr18-23544943-A-AC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

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+16dupG		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+16_1947+17insG		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+16_1998+17insG		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+16_1947+17insG		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 22879 AN: 104660 Hom.: 5476 Cov.: 0

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.173 AC: 159477 AN: 921926 Hom.: 6285 Cov.: 19 AF XY: 0.175 AC XY: 82374 AN XY: 471122

African (AFR) AF: 0.166 AC: 4221 AN: 25368

American (AMR) AF: 0.126 AC: 4538 AN: 35958

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 4855 AN: 20740

East Asian (EAS) AF: 0.0437 AC: 1156 AN: 26458

South Asian (SAS) AF: 0.186 AC: 13193 AN: 70786

European-Finnish (FIN) AF: 0.170 AC: 6749 AN: 39690

Middle Eastern (MID) AF: 0.223 AC: 939 AN: 4220

European-Non Finnish (NFE) AF: 0.177 AC: 116648 AN: 658464

Other (OTH) AF: 0.178 AC: 7178 AN: 40242

GnomAD4 genome AF: 0.218 AC: 22872 AN: 104708 Hom.: 5470 Cov.: 0 AF XY: 0.218 AC XY: 10823 AN XY: 49606

African (AFR) AF: 0.175 AC: 5502 AN: 31402

American (AMR) AF: 0.225 AC: 2012 AN: 8946

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 887 AN: 2802

East Asian (EAS) AF: 0.0227 AC: 82 AN: 3614

South Asian (SAS) AF: 0.247 AC: 749 AN: 3030

European-Finnish (FIN) AF: 0.221 AC: 1095 AN: 4952

Middle Eastern (MID) AF: 0.343 AC: 74 AN: 216

European-Non Finnish (NFE) AF: 0.249 AC: 11865 AN: 47658

Other (OTH) AF: 0.240 AC: 348 AN: 1448

Alfa AF: 0.142 Hom.: 365

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Niemann-Pick disease, type C1 (6)
-	-	5	not specified (5)
-	-	1	not provided (1)
-	-	1	NPC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs3837910; hg19: chr18-21124907; COSMIC: COSV52582248; COSMIC: COSV52582248;