rs142654383

Variant names:

• chr18-23518925-A-C
• NM_013326.5:c.689A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-23518925-A-C
• chr18-23518925-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013326.5(RMC1):​c.689A>C​(p.His230Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RMC1 NM_013326.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMC1	NM_013326.5	c.689A>C	p.His230Pro	missense_variant	Exon 8 of 20	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMC1	ENST00000269221.8	c.689A>C	p.His230Pro	missense_variant	Exon 8 of 20	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.545A>C	p.His182Pro	missense_variant	Exon 6 of 18	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.689A>C	p.His230Pro	missense_variant	Exon 8 of 20	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*346A>C		non_coding_transcript_exon_variant	Exon 7 of 19	2		ENSP00000467852.1
RMC1	ENST00000589215.5	n.*346A>C		3_prime_UTR_variant	Exon 7 of 19	2		ENSP00000467852.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0076	T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.88	T
PROVEAN	Benign	-0.79	.;N;.
REVEL	Uncertain	0.44
Sift	Benign	0.27	.;T;.
Sift4G	Benign	0.25	T;T;T
Polyphen		0.91	.;P;.
Vest4		0.80
MutPred		0.47		.;Loss of helix (P = 0.0138);.;
MVP		0.44
MPC		0.60
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.76

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-21098889;