chr4-153295396-C-T

Variant names:

• chr4-153295396-C-T
• rs35333794
• NM_015271.5:c.870C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015271.5(TRIM2):​c.870C>T​(p.Asn290Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,614,112 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.017 (300 hom.)
• Consequence: TRIM2 NM_015271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.21
• Publications: 6 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-153295396-C-T is Benign according to our data. Variant chr4-153295396-C-T is described in ClinVar as Benign. ClinVar VariationId is 474616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.012 (1830/152338) while in subpopulation AMR AF = 0.0176 (269/15312). AF 95% confidence interval is 0.0158. There are 18 homozygotes in GnomAd4. There are 867 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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.870C>T	p.Asn290Asn	synonymous	Exon 6 of 12	NP_056086.2	Q9C040-2
	TRIM2	NM_001375488.1		c.963C>T	p.Asn321Asn	synonymous	Exon 7 of 13	NP_001362417.1
	TRIM2	NM_001375489.1		c.960C>T	p.Asn320Asn	synonymous	Exon 7 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.870C>T	p.Asn290Asn	synonymous	Exon 6 of 12	ENSP00000339659.5	Q9C040-2
	ENSG00000288637	ENST00000675838.1		c.789C>T	p.Asn263Asn	synonymous	Exon 6 of 18	ENSP00000501593.1	A0A6Q8PF18
	TRIM2	ENST00000437508.7	TSL:1	c.789C>T	p.Asn263Asn	synonymous	Exon 6 of 12	ENSP00000415812.2	Q9C040-1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1831 AN: 152220 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0149 AC: 3735 AN: 250904 AF XY: 0.0144

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00299

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0174 AC: 25436 AN: 1461774 Hom.: 300 Cov.: 30 AF XY: 0.0169 AC XY: 12318 AN XY: 727154

African (AFR) AF: 0.00245 AC: 82 AN: 33480

American (AMR) AF: 0.0363 AC: 1624 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26134

East Asian (EAS) AF: 0.0130 AC: 517 AN: 39696

South Asian (SAS) AF: 0.00767 AC: 661 AN: 86232

European-Finnish (FIN) AF: 0.0118 AC: 632 AN: 53408

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 21005 AN: 1111950

Other (OTH) AF: 0.0141 AC: 853 AN: 60392

GnomAD4 genome AF: 0.0120 AC: 1830 AN: 152338 Hom.: 18 Cov.: 32 AF XY: 0.0116 AC XY: 867 AN XY: 74498

African (AFR) AF: 0.00349 AC: 145 AN: 41582

American (AMR) AF: 0.0176 AC: 269 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5176

South Asian (SAS) AF: 0.00641 AC: 31 AN: 4834

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1110 AN: 68016

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0150 Hom.: 33

Bravo AF: 0.0121

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0144

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease type 2R (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.7
DANN	Benign	0.91
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs35333794; hg19: chr4-154216548;