rs6507720

Variant names:

• chr18-23539327-A-G
• rs6507720
• NM_000271.5:c.2911+28T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-23539327-A-G
• chr18-23539327-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.2911+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,523,196 control chromosomes in the GnomAD database, including 198,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24469 hom., cov: 33)
  • Exomes 𝑓: 0.50 (173884 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.445

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-23539327-A-G is Benign according to our data. Variant chr18-23539327-A-G is described in ClinVar as [Benign]. Clinvar id is 255695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23539327-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2911+28T>C		intron_variant	Intron 19 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2911+28T>C		intron_variant	Intron 19 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1987+28T>C		intron_variant	Intron 12 of 17	2		ENSP00000467636.1
NPC1	ENST00000591075.1	n.544+28T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84552 AN: 152008 Hom.: 24425 Cov.: 33

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.493

GnomAD3 exomes AF: 0.525 AC: 129031 AN: 245706 Hom.: 35166 AF XY: 0.512 AC XY: 67950 AN XY: 132600

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.623

Gnomad SAS exome AF: 0.498

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.499 AC: 684094 AN: 1371070 Hom.: 173884 Cov.: 21 AF XY: 0.495 AC XY: 340004 AN XY: 686280

Gnomad4 AFR exome AF: 0.703

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.657

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.557 AC: 84661 AN: 152126 Hom.: 24469 Cov.: 33 AF XY: 0.557 AC XY: 41421 AN XY: 74364

Gnomad4 AFR AF: 0.703

Gnomad4 AMR AF: 0.603

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.500

Alfa AF: 0.468 Hom.: 17738

Bravo AF: 0.572

Asia WGS AF: 0.571 AC: 1984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: 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	-0.86
CADD	Benign	1.1
DANN	Benign	0.39

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: rs6507720; hg19: chr18-21119291; COSMIC: COSV52577256; COSMIC: COSV52577256;