rs75936194

Variant names:

• chr14-74480003-G-A
• rs75936194
• NM_006432.5:c.*271C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-74480003-G-A
• chr14-74480003-G-T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 1.83
• 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.*271C>T		3_prime_UTR	Exon 5 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.*615C>T		3_prime_UTR	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.*271C>T		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.*271C>T		3_prime_UTR	Exon 5 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000238633.6	TSL:3	c.*271C>T		3_prime_UTR	Exon 5 of 5	ENSP00000238633.2	J3KMY5
	NPC2	ENST00000541064.5	TSL:2	c.*271C>T		3_prime_UTR	Exon 4 of 4	ENSP00000442488.1	P61916-2

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

African (AFR) AF: 0.000755 AC: 21 AN: 27832

American (AMR) AF: 0.0344 AC: 761 AN: 22108

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 3 AN: 19512

East Asian (EAS) AF: 0.00269 AC: 83 AN: 30872

South Asian (SAS) AF: 0.00157 AC: 102 AN: 65112

European-Finnish (FIN) AF: 0.0131 AC: 338 AN: 25806

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5134

European-Non Finnish (NFE) AF: 0.000245 AC: 250 AN: 1021528

Other (OTH) AF: 0.00198 AC: 103 AN: 51986

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

African (AFR) AF: 0.00176 AC: 73 AN: 41420

American (AMR) AF: 0.0321 AC: 490 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4780

European-Finnish (FIN) AF: 0.0163 AC: 172 AN: 10564

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

European-Non Finnish (NFE) AF: 0.000633 AC: 43 AN: 67944

Other (OTH) AF: 0.00668 AC: 14 AN: 2096

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00628

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.5
DANN	Benign	0.49
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs75936194; hg19: chr14-74946706;