14-74480003-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006432.5(NPC2):c.*271C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,421,790 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: NPC2 NM_006432.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83

Genes affected

NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

SYNDIG1L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-74480003-G-A is Benign according to our data. Variant chr14-74480003-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00535 (813/151900) while in subpopulation AMR AF= 0.0321 (490/15248). AF 95% confidence interval is 0.0298. There are 14 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.*271C>T		3_prime_UTR_variant	5/5	ENST00000555619.6
SYNDIG1L	XM_017021600.2	c.-5757C>T		5_prime_UTR_variant	1/4
NPC2	NM_001363688.1	c.*615C>T		3_prime_UTR_variant	4/4
NPC2	NM_001375440.1	c.*271C>T		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.*271C>T		3_prime_UTR_variant	5/5	1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 805 AN: 151782 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00675

GnomAD4 exome AF: 0.00131 AC: 1662 AN: 1269890 Hom.: 30 Cov.: 30 AF XY: 0.00124 AC XY: 771 AN XY: 619766

Gnomad4 AFR exome AF: 0.000755

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00269

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.00535 AC: 813 AN: 151900 Hom.: 14 Cov.: 32 AF XY: 0.00641 AC XY: 476 AN XY: 74236

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.00668

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00628

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Niemann-Pick disease, type C1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.5
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs75936194; hg19: chr14-74946706;