NM_000271.5:c.1947+10G>C

Variant names:

• chr18-23544950-C-G
• rs71534236
• NM_000271.5:c.1947+10G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000271.5(NPC1):​c.1947+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,415,958 control chromosomes in the GnomAD database, including 670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (107 hom., cov: 27)
  • Exomes 𝑓: 0.0090 (563 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.104
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-23544950-C-G is Benign according to our data. Variant chr18-23544950-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00704 (1012/143798) while in subpopulation NFE AF = 0.0104 (660/63298). AF 95% confidence interval is 0.00977. There are 107 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 107 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+10G>C		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+10G>C		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+10G>C		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+10G>C		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1011 AN: 143684 Hom.: 107 Cov.: 27

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00708

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00149

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00358

GnomAD2 exomes AF: 0.00788 AC: 1923 AN: 244166 AF XY: 0.00797

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00690

GnomAD4 exome AF: 0.00900 AC: 11455 AN: 1272160 Hom.: 563 Cov.: 26 AF XY: 0.00886 AC XY: 5669 AN XY: 640090

African (AFR) AF: 0.00102 AC: 32 AN: 31238

American (AMR) AF: 0.00170 AC: 73 AN: 42970

Ashkenazi Jewish (ASJ) AF: 0.000359 AC: 9 AN: 25068

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34646

South Asian (SAS) AF: 0.00476 AC: 390 AN: 81850

European-Finnish (FIN) AF: 0.0238 AC: 1167 AN: 49066

Middle Eastern (MID) AF: 0.000916 AC: 5 AN: 5458

European-Non Finnish (NFE) AF: 0.00995 AC: 9434 AN: 948374

Other (OTH) AF: 0.00643 AC: 344 AN: 53490

GnomAD4 genome AF: 0.00704 AC: 1012 AN: 143798 Hom.: 107 Cov.: 27 AF XY: 0.00740 AC XY: 521 AN XY: 70358

African (AFR) AF: 0.00126 AC: 51 AN: 40346

American (AMR) AF: 0.00270 AC: 39 AN: 14458

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 5 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00418 AC: 18 AN: 4310

European-Finnish (FIN) AF: 0.0226 AC: 226 AN: 10004

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

European-Non Finnish (NFE) AF: 0.0104 AC: 660 AN: 63298

Other (OTH) AF: 0.00355 AC: 7 AN: 1972

Alfa AF: 0.00454 Hom.: 17

Bravo AF: 0.00467

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)
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.53
DANN	Benign	0.30
PhyloP100		0.10
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: rs71534236; hg19: chr18-21124914; COSMIC: COSV106369640; COSMIC: COSV106369640;