rs6088316

Variant names:

• chr20-33839036-A-G
• rs6088316
• NM_176812.5:c.191-9431A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_176812.5(CHMP4B):​c.191-9431A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,166 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1218 hom., cov: 32)
• Consequence: CHMP4B NM_176812.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 9 publications found

Genes affected

CHMP4B (HGNC:16171): (charged multivesicular body protein 4B) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein (CHMP) protein family. The protein is part of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The ESCRT machinery also functions in the final abscisson stage of cytokinesis and in the budding of enveloped viruses such as HIV-1. The three proteins of the CHMP4 subfamily interact with programmed cell death 6 interacting protein (PDCD6IP, also known as ALIX), which also functions in the ESCRT pathway. The CHMP4 proteins assemble into membrane-attached 5-nm filaments that form circular scaffolds and promote or stabilize outward budding. These polymers are proposed to help generate the luminal vesicles of multivesicular bodies. Mutations in this gene result in autosomal dominant posterior polar cataracts.[provided by RefSeq, Oct 2009]

CHMP4B Gene-Disease associations (from GenCC):

• cataract 31 multiple types

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4B	NM_176812.5	c.191-9431A>G		intron_variant	Intron 1 of 4	ENST00000217402.3	NP_789782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4B	ENST00000217402.3	c.191-9431A>G		intron_variant	Intron 1 of 4	1	NM_176812.5	ENSP00000217402.2

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16402 AN: 152048 Hom.: 1218 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0947

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.0923

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16399 AN: 152166 Hom.: 1218 Cov.: 32 AF XY: 0.104 AC XY: 7757 AN XY: 74398

African (AFR) AF: 0.0286 AC: 1188 AN: 41546

American (AMR) AF: 0.0945 AC: 1444 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3470

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5182

South Asian (SAS) AF: 0.143 AC: 688 AN: 4810

European-Finnish (FIN) AF: 0.0918 AC: 972 AN: 10590

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11248 AN: 67970

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.149 Hom.: 2036

Bravo AF: 0.102

Asia WGS AF: 0.0790 AC: 277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6088316; hg19: chr20-32426842;