18-11851907-G-T

Variant names:

• chr18-11851907-G-T
• rs981760833
• NM_020412.5:c.396G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020412.5(CHMP1B):​c.396G>T​(p.Met132Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M132V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHMP1B NM_020412.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

CHMP1B (HGNC:24287): (charged multivesicular body protein 1B) CHMP1B belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

CHMP1B-AS1 (HGNC:52778): (CHMP1B antisense RNA 1)

ENSG00000296678 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020412.5. 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
	CHMP1B	NM_020412.5	MANE Select	c.396G>T	p.Met132Ile	missense	Exon 1 of 1	NP_065145.2
	GNAL	NM_182978.4	MANE Select	c.723-10488G>T		intron	N/A	NP_892023.1	P38405-2
	GNAL	NM_001369387.1	MANE Plus Clinical	c.492-10488G>T		intron	N/A	NP_001356316.1	A8K1Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP1B	ENST00000526991.3	TSL:6 MANE Select	c.396G>T	p.Met132Ile	missense	Exon 1 of 1	ENSP00000432279.1	Q7LBR1
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.723-10488G>T		intron	N/A	ENSP00000334051.5	P38405-2
	GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.492-10488G>T		intron	N/A	ENSP00000408489.2	P38405-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.013	D
PhyloP100		9.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.50
Sift	Benign	0.046	D
Sift4G	Benign	0.084	T
Polyphen		0.71	P
Vest4		0.70
MutPred		0.54		Loss of loop (P = 0.1258)
MVP		0.92
MPC		1.4
ClinPred		0.96	D
GERP RS		5.6
PromoterAI		-0.039	Neutral
Varity_R		0.60
gMVP		0.74
Mutation Taster		=23/77	disease causing

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: rs981760833; hg19: chr18-11851906;