NM_013326.5:c.1230C>G

Variant names:

• chr18-23527835-C-G
• rs141781475
• NM_013326.5:c.1230C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_013326.5(RMC1):​c.1230C>G​(p.Ala410Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,614,066 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (10 hom.)
• Consequence: RMC1 NM_013326.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28
• Publications: 1 publications found

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]

NPC1 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 18-23527835-C-G is Benign according to our data. Variant chr18-23527835-C-G is described in ClinVar as [Benign]. Clinvar id is 778149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMC1	NM_013326.5	c.1230C>G	p.Ala410Ala	synonymous_variant	Exon 14 of 20	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMC1	ENST00000269221.8	c.1230C>G	p.Ala410Ala	synonymous_variant	Exon 14 of 20	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.1086C>G	p.Ala362Ala	synonymous_variant	Exon 12 of 18	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.1230C>G	p.Ala410Ala	synonymous_variant	Exon 14 of 20	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*887C>G		non_coding_transcript_exon_variant	Exon 13 of 19	2		ENSP00000467852.1
RMC1	ENST00000589215.5	n.*887C>G		3_prime_UTR_variant	Exon 13 of 19	2		ENSP00000467852.1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152130 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00218 AC: 549 AN: 251420 AF XY: 0.00197

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00228 AC: 3339 AN: 1461818 Hom.: 10 Cov.: 31 AF XY: 0.00220 AC XY: 1603 AN XY: 727208

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0137 AC: 729 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00223 AC: 2482 AN: 1111982

Other (OTH) AF: 0.00195 AC: 118 AN: 60390

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152248 Hom.: 4 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74434

African (AFR) AF: 0.000481 AC: 20 AN: 41538

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000854

EpiCase AF: 0.00202

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		1.3
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: rs141781475; hg19: chr18-21107799;