14-74480389-C-A

Variant names:

• chr14-74480389-C-A
• rs10220503
• ENST00000557510.5:c.*229G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001363688.1(NPC2):​c.*229G>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 0.00247 in 1,043,482 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: NPC2 NM_001363688.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.101
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-74480389-C-A is Benign according to our data. Variant chr14-74480389-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1213457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1551/152306) while in subpopulation AFR AF = 0.0357 (1482/41564). AF 95% confidence interval is 0.0341. There are 38 homozygotes in GnomAd4. There are 731 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363688.1. 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.442-101G>T		intron	N/A	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.*229G>T		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.364-101G>T		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.*229G>T		3_prime_UTR	Exon 4 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.442-101G>T		intron	N/A	ENSP00000451112.2	P61916-1
	NPC2	ENST00000553490.5	TSL:2	c.458-101G>T		intron	N/A	ENSP00000451180.1	G3V3D1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1542 AN: 152188 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00115 AC: 1029 AN: 891176 Hom.: 15 Cov.: 13 AF XY: 0.000998 AC XY: 466 AN XY: 466904

African (AFR) AF: 0.0369 AC: 825 AN: 22336

American (AMR) AF: 0.00178 AC: 78 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.0000444 AC: 1 AN: 22536

East Asian (EAS) AF: 0.00 AC: 0 AN: 37036

South Asian (SAS) AF: 0.0000670 AC: 5 AN: 74590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53014

Middle Eastern (MID) AF: 0.000996 AC: 3 AN: 3012

European-Non Finnish (NFE) AF: 0.0000202 AC: 12 AN: 593614

Other (OTH) AF: 0.00254 AC: 105 AN: 41340

GnomAD4 genome AF: 0.0102 AC: 1551 AN: 152306 Hom.: 38 Cov.: 32 AF XY: 0.00982 AC XY: 731 AN XY: 74474

African (AFR) AF: 0.0357 AC: 1482 AN: 41564

American (AMR) AF: 0.00320 AC: 49 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00359 Hom.: 7

Bravo AF: 0.0116

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.10
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

Other links and lift over

dbSNP: rs10220503; hg19: chr14-74947092;