ENST00000557510.5:c.*326A>C

Variant names:

• chr14-74480292-T-G
• rs114950106
• ENST00000557510.5:c.*326A>C

Variant summary

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

The ENST00000557510.5(NPC2):​c.*326A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,074 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (100 hom.)
• Consequence: NPC2 ENST00000557510.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00008026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.17
• Publications: 2 publications found

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:32388): (synapse differentiation inducing 1 like) Predicted to be located in Golgi apparatus. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

MIR4709 (HGNC:41690): (microRNA 4709) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-74480292-T-G is Benign according to our data. Variant chr14-74480292-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00767 (1168/152286) while in subpopulation SAS AF = 0.0315 (152/4822). AF 95% confidence interval is 0.0274. There are 19 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557510.5. 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
	NPC2	NM_006432.5	MANE Select	c.442-4A>C		splice_region intron	N/A	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.*326A>C		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.364-4A>C		splice_region intron	N/A	NP_001362369.1	P61916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000557510.5	TSL:1	c.*326A>C		3_prime_UTR	Exon 4 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.442-4A>C		splice_region intron	N/A	ENSP00000451112.2	P61916-1
	NPC2	ENST00000553490.5	TSL:2	c.458-4A>C		splice_region intron	N/A	ENSP00000451180.1	G3V3D1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152168 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00621 AC: 1547 AN: 249162 AF XY: 0.00741

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00285 AC: 4158 AN: 1459788 Hom.: 100 Cov.: 30 AF XY: 0.00374 AC XY: 2719 AN XY: 726380

African (AFR) AF: 0.0259 AC: 864 AN: 33408

American (AMR) AF: 0.000783 AC: 35 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39692

South Asian (SAS) AF: 0.0342 AC: 2948 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00355 AC: 19 AN: 5348

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1110588

Other (OTH) AF: 0.00337 AC: 203 AN: 60272

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152286 Hom.: 19 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74464

African (AFR) AF: 0.0231 AC: 959 AN: 41556

American (AMR) AF: 0.00189 AC: 29 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00742

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Niemann-Pick disease, type C2 (2)
-	-	2	not specified (2)
-	-	1	Niemann-Pick disease, type C1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.56
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.17		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: rs114950106; hg19: chr14-74946995;