chr18-23515989-A-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_013326.5(RMC1):c.542A>G(p.His181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,613,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00096 ( 2 hom. )
Consequence
RMC1
NM_013326.5 missense
NM_013326.5 missense
Scores
2
12
Clinical Significance
Conservation
PhyloP100: 3.38
Genes affected
RMC1 (HGNC:24326): (regulator of MON1-CCZ1) This gene encodes a colon cancer associated protein. [provided by RefSeq, Jan 2013]
NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.049025625).
BS2
?
High AC in GnomAd at 85 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RMC1 | NM_013326.5 | c.542A>G | p.His181Arg | missense_variant | 6/20 | ENST00000269221.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RMC1 | ENST00000269221.8 | c.542A>G | p.His181Arg | missense_variant | 6/20 | 1 | NM_013326.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000560 AC: 85AN: 151840Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000604 AC: 152AN: 251460Hom.: 1 AF XY: 0.000662 AC XY: 90AN XY: 135900
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GnomAD4 exome AF: 0.000962 AC: 1406AN: 1461880Hom.: 2 Cov.: 31 AF XY: 0.000923 AC XY: 671AN XY: 727244
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2021 | The c.542A>G (p.H181R) alteration is located in exon 6 (coding exon 6) of the C18orf8 gene. This alteration results from a A to G substitution at nucleotide position 542, causing the histidine (H) at amino acid position 181 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
Sift4G
Benign
T;T;T
Polyphen
0.016
.;B;.
Vest4
MVP
MPC
0.47
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at