14-74480021-TAA-TAAA

Variant names:

• chr14-74480021-T-TA
• rs369932535
• NM_006432.5:c.*252dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_006432.5(NPC2):​c.*252dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,356,294 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (1 hom.)
• Consequence: NPC2 NM_006432.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00302 (452/149802) while in subpopulation AFR AF = 0.00729 (298/40886). AF 95% confidence interval is 0.00661. There are 1 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*252dupT		3_prime_UTR	Exon 5 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.*596dupT		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.*252dupT		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.*252dupT		3_prime_UTR	Exon 5 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000238633.6	TSL:3	c.*252dupT		3_prime_UTR	Exon 5 of 5	ENSP00000238633.2	J3KMY5
	NPC2	ENST00000541064.5	TSL:2	c.*252dupT		3_prime_UTR	Exon 4 of 4	ENSP00000442488.1	P61916-2

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 454 AN: 149686 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.000875

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000197

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00195

GnomAD4 exome AF: 0.00370 AC: 4464 AN: 1206492 Hom.: 1 Cov.: 31 AF XY: 0.00385 AC XY: 2272 AN XY: 590346

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0118 AC: 309 AN: 26294

American (AMR) AF: 0.00797 AC: 173 AN: 21712

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 140 AN: 19530

East Asian (EAS) AF: 0.00698 AC: 207 AN: 29654

South Asian (SAS) AF: 0.00241 AC: 152 AN: 63104

European-Finnish (FIN) AF: 0.00679 AC: 180 AN: 26516

Middle Eastern (MID) AF: 0.00702 AC: 35 AN: 4984

European-Non Finnish (NFE) AF: 0.00316 AC: 3055 AN: 965466

Other (OTH) AF: 0.00433 AC: 213 AN: 49232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00302 AC: 452 AN: 149802 Hom.: 1 Cov.: 32 AF XY: 0.00304 AC XY: 222 AN XY: 73046

African (AFR) AF: 0.00729 AC: 298 AN: 40886

American (AMR) AF: 0.00460 AC: 69 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.000875 AC: 3 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4686

European-Finnish (FIN) AF: 0.000197 AC: 2 AN: 10170

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 72 AN: 67264

Other (OTH) AF: 0.00193 AC: 4 AN: 2072

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
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: rs369932535; hg19: chr14-74946724; COSMIC: COSV99467245; COSMIC: COSV99467245;