18-11851600-A-G

Variant names:

• chr18-11851600-A-G
• rs1053039371
• NM_020412.5:c.89A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020412.5(CHMP1B):​c.89A>G​(p.Lys30Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP1B NM_020412.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36062467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP1B	NM_020412.5	c.89A>G	p.Lys30Arg	missense_variant	Exon 1 of 1	ENST00000526991.3	NP_065145.2
GNAL	NM_182978.4	c.723-10795A>G		intron_variant	Intron 5 of 11	ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.492-10795A>G		intron_variant	Intron 5 of 11	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP1B	ENST00000526991.3	c.89A>G	p.Lys30Arg	missense_variant	Exon 1 of 1	6	NM_020412.5	ENSP00000432279.1
GNAL	ENST00000334049.11	c.723-10795A>G		intron_variant	Intron 5 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.492-10795A>G		intron_variant	Intron 5 of 11	1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247168 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726814

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000555 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89A>G (p.K30R) alteration is located in exon 1 (coding exon 1) of the CHMP1B gene. This alteration results from a A to G substitution at nucleotide position 89, causing the lysine (K) at amino acid position 30 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.45	T
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.013	B
Vest4		0.52
MVP		0.89
MPC		0.53
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs1053039371; hg19: chr18-11851599;