chr18-23560447-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_000271.5(NPC1):āc.665A>Gā(p.Asn222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00537 in 1,614,122 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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NPC1 | NM_000271.5 | c.665A>G | p.Asn222Ser | missense_variant | Exon 6 of 25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00332 AC: 506AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00336 AC: 842AN: 250650Hom.: 0 AF XY: 0.00360 AC XY: 488AN XY: 135548
GnomAD4 exome AF: 0.00558 AC: 8164AN: 1461800Hom.: 37 Cov.: 32 AF XY: 0.00556 AC XY: 4043AN XY: 727198
GnomAD4 genome AF: 0.00332 AC: 506AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.00314 AC XY: 234AN XY: 74494
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:2Benign:2Other:1
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GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:2Benign:2
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NPC1: BS2 -
BS1 -
not specified Benign:2
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Variant summary: NPC1 c.665A>G (p.Asn222Ser) results in a conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 250650 control chromosomes (gnomAD), predominantly at a frequency of 0.0051 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.0027), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin.c.665A>G has been reported in the literature in multiple individuals presenting with varying phenotypes from Niemann-Pick Disease Type C, late-onset/adult and late infantile forms, familial epileptogenic encephalopathy with a peculiar form of degenerative glial tauopathy, neonatal cholestasis, epilepsy and psycotic symptoms, splenomegaly, and low and high HDL-C (Cupidi_2018, DeCastro-Oros_2017, Fancello_2009, Imrie_2007, Park_2003, Romanello_2016, Sadananda_2015, Stampfer_2013, Wassif_2016, Dardis_2020, Touma_2020 and Lopez de Fruto_2021). The variant has presented in isolation (no second NPC1 allele identified), as a compound heterozygote with another pathogenic NPC1 variant (I1061T, P1007A) and in co-occurrence with two additional pathogenic NPC1 variants (I1061T/R958Q - phase is not known). The variant was also detected in homozygous state in one young obese patient without other phenotypic information provided (Liu_2017). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein was secreted and showed normal behavior and cellular localization, while protein expression and cholesterol transporting ability were similar to wild type (Liu_2017, Infante_2008). The following publications have been ascertained in the context of this evaluation (PMID: 32138288, 28222799, 30153451, 19252935, 17160617, 17989072, 28130309, 32745579, 12955717, 26790753, 26255038, 23433426, 33990640, 25764212). Nine ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, four as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
NPC1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at