rs879253863

Variant names:

• chr4-153324126-A-C
• rs879253863
• NM_015271.5:c.2000A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_015271.5(TRIM2):​c.2000A>C​(p.Asp667Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.10
• Publications: 7 publications found

Genes affected

TRIM2 (HGNC:15974): (tripartite motif containing 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic filaments. It plays a neuroprotective role and functions as an E3-ubiquitin ligase in proteasome-mediated degradation of target proteins. Mutations in this gene can cause early-onset axonal neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

TRIM2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2R

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000288637 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 4-153324126-A-C is Pathogenic according to our data. Variant chr4-153324126-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 243075.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015271.5. 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
	TRIM2	NM_015271.5	MANE Select	c.2000A>C	p.Asp667Ala	missense	Exon 10 of 12	NP_056086.2	Q9C040-2
	TRIM2	NM_001375488.1		c.2093A>C	p.Asp698Ala	missense	Exon 11 of 13	NP_001362417.1
	TRIM2	NM_001375489.1		c.2090A>C	p.Asp697Ala	missense	Exon 11 of 13	NP_001362418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM2	ENST00000338700.10	TSL:1 MANE Select	c.2000A>C	p.Asp667Ala	missense	Exon 10 of 12	ENSP00000339659.5	Q9C040-2
	ENSG00000288637	ENST00000675838.1		c.1919A>C	p.Asp640Ala	missense	Exon 10 of 18	ENSP00000501593.1	A0A6Q8PF18
	TRIM2	ENST00000437508.7	TSL:1	c.1919A>C	p.Asp640Ala	missense	Exon 10 of 12	ENSP00000415812.2	Q9C040-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Charcot-Marie-Tooth disease type 2R (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Gain of sheet (P = 0.1539)
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs879253863; hg19: chr4-154245278;