14-74480120-C-T

Variant names:

• chr14-74480120-C-T
• rs142355730
• NM_006432.5:c.*154G>A

Variant summary

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

The NM_006432.5(NPC2):​c.*154G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,562,398 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: NPC2 NM_006432.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.103
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004185885).
• BP6: Variant 14-74480120-C-T is Benign according to our data. Variant chr14-74480120-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1300451.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00295 (449/152174) while in subpopulation AFR AF = 0.01 (416/41510). AF 95% confidence interval is 0.00923. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006432.5. 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.*154G>A		3_prime_UTR	Exon 5 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.*498G>A		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.*154G>A		3_prime_UTR	Exon 4 of 4	NP_001362369.1	P61916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.*154G>A		3_prime_UTR	Exon 5 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000553490.5	TSL:2	c.626G>A	p.Arg209Gln	missense	Exon 5 of 5	ENSP00000451180.1	G3V3D1
	NPC2	ENST00000556009.5	TSL:5	c.*154G>A		3_prime_UTR	Exon 5 of 5	ENSP00000450502.1	H0YIZ1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000882

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000621 AC: 108 AN: 174000 AF XY: 0.000567

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000674

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000281 AC: 396 AN: 1410224 Hom.: 3 Cov.: 32 AF XY: 0.000258 AC XY: 180 AN XY: 697670

African (AFR) AF: 0.00921 AC: 296 AN: 32132

American (AMR) AF: 0.000534 AC: 20 AN: 37452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25292

East Asian (EAS) AF: 0.00 AC: 0 AN: 36702

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000303 AC: 33 AN: 1089340

Other (OTH) AF: 0.000783 AC: 46 AN: 58784

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00276 AC XY: 205 AN XY: 74380

African (AFR) AF: 0.0100 AC: 416 AN: 41510

American (AMR) AF: 0.00137 AC: 21 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00329

ExAC AF: 0.000662 AC: 79

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	5.1
DANN	Benign	0.56
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.53	T
PhyloP100		-0.10
PROVEAN	Benign	0.0	N
REVEL	Benign	0.031
Sift	Benign	0.38	T
MVP		0.65
ClinPred		0.0045	T
GERP RS		-0.036
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: rs142355730; hg19: chr14-74946823;