chr18-23544950-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000271.5(NPC1):​c.1947+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,415,988 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 27)
  • Exomes 𝑓: 0.000084 (2 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.104

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-23544950-C-A is Benign according to our data. Variant chr18-23544950-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495787.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+10G>T		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+10G>T		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+10G>T		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+10G>T		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 27 AN: 143688 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000693

Gnomad ASJ AF: 0.000595

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000695

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000948

Gnomad OTH AF: 0.000512

GnomAD2 exomes AF: 0.000119 AC: 29 AN: 244166 AF XY: 0.000106

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000636

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 107 AN: 1272186 Hom.: 2 Cov.: 26 AF XY: 0.0000922 AC XY: 59 AN XY: 640108

Gnomad4 AFR exome AF: 0.000736 AC: 23 AN: 31238

Gnomad4 AMR exome AF: 0.000163 AC: 7 AN: 42970

Gnomad4 ASJ exome AF: 0.000120 AC: 3 AN: 25068

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 34646

Gnomad4 SAS exome AF: 0.000110 AC: 9 AN: 81850

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49066

Gnomad4 NFE exome AF: 0.0000590 AC: 56 AN: 948400

Gnomad4 Remaining exome AF: 0.0000935 AC: 5 AN: 53490

GnomAD4 genome AF: 0.000202 AC: 29 AN: 143802 Hom.: 1 Cov.: 27 AF XY: 0.000171 AC XY: 12 AN XY: 70360

Gnomad4 AFR AF: 0.000372 AC: 0.000371784 AN: 0.000371784

Gnomad4 AMR AF: 0.0000692 AC: 0.0000691659 AN: 0.0000691659

Gnomad4 ASJ AF: 0.000595 AC: 0.00059453 AN: 0.00059453

Gnomad4 EAS AF: 0.000204 AC: 0.000203749 AN: 0.000203749

Gnomad4 SAS AF: 0.000696 AC: 0.000696056 AN: 0.000696056

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000948 AC: 0.0000947897 AN: 0.0000947897

Gnomad4 OTH AF: 0.000507 AC: 0.000507099 AN: 0.000507099

Alfa AF: 0.0000366 Hom.: 17

Bravo AF: 0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:1 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 21, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.97
DANN	Benign	0.39
Mutation Taster		=100/0	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs71534236; hg19: chr18-21124914;