rs200912994

Variant names:

• chr3-87240692-C-T
• rs200912994
• NM_014043.4:c.35-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-87240692-C-T
• chr3-87240692-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_014043.4(CHMP2B):​c.35-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,586,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CHMP2B NM_014043.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.881
• Publications: 0 publications found

Genes affected

CHMP2B (HGNC:24537): (charged multivesicular body protein 2B) This gene encodes a component of the heteromeric ESCRT-III complex (Endosomal Sorting Complex Required for Transport III) that functions in the recycling or degradation of cell surface receptors. ESCRT-III functions in the concentration and invagination of ubiquitinated endosomal cargos into intralumenal vesicles. The protein encoded by this gene is found as a monomer in the cytosol or as an oligomer in ESCRT-III complexes on endosomal membranes. It is expressed in neurons of all major regions of the brain. Mutations in this gene result in one form of familial frontotemporal lobar degeneration. [provided by RefSeq, Jul 2008]

CHMP2B Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• amyotrophic lateral sclerosis type 17

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 3-87240692-C-T is Benign according to our data. Variant chr3-87240692-C-T is described in ClinVar as Benign. ClinVar VariationId is 704275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 186 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014043.4. 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
	CHMP2B	NM_014043.4	MANE Select	c.35-7C>T		splice_region intron	N/A	NP_054762.2
	CHMP2B	NM_001410777.1		c.131-7C>T		splice_region intron	N/A	NP_001397706.1
	CHMP2B	NM_001244644.2		c.4-5022C>T		intron	N/A	NP_001231573.1	Q9UQN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.35-7C>T		splice_region intron	N/A	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.83-7C>T		splice_region intron	N/A	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.83-7C>T		splice_region intron	N/A	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000355 AC: 89 AN: 251010 AF XY: 0.000243

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000110 AC: 158 AN: 1433970 Hom.: 0 Cov.: 26 AF XY: 0.0000866 AC XY: 62 AN XY: 715546

African (AFR) AF: 0.00368 AC: 121 AN: 32850

American (AMR) AF: 0.000381 AC: 17 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5716

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1086700

Other (OTH) AF: 0.000286 AC: 17 AN: 59496

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74406

African (AFR) AF: 0.00412 AC: 171 AN: 41522

American (AMR) AF: 0.000654 AC: 10 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.00150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CHMP2B-related disorder (1)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.022
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: rs200912994; hg19: chr3-87289842;