2-96275128-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_014014.5(SNRNP200):ā€‹c.6295A>Gā€‹(p.Thr2099Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000099 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

SNRNP200
NM_014014.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14
Variant links:
Genes affected
SNRNP200 (HGNC:30859): (small nuclear ribonucleoprotein U5 subunit 200) Pre-mRNA splicing is catalyzed by the spliceosome, a complex of specialized RNA and protein subunits that removes introns from a transcribed pre-mRNA segment. The spliceosome consists of small nuclear RNA proteins (snRNPs) U1, U2, U4, U5 and U6, together with approximately 80 conserved proteins. U5 snRNP contains nine specific proteins. This gene encodes one of the U5 snRNP-specific proteins. This protein belongs to the DEXH-box family of putative RNA helicases. It is a core component of U4/U6-U5 snRNPs and appears to catalyze an ATP-dependent unwinding of U4/U6 RNA duplices. Mutations in this gene cause autosomal-dominant retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of these variants has not been determined. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SNRNP200. . Gene score misZ 5.9363 (greater than the threshold 3.09). Trascript score misZ 8.7488 (greater than threshold 3.09). GenCC has associacion of gene with retinitis pigmentosa 33, SNRNP200-related dominant retinopathy, retinitis pigmentosa.
BP4
Computational evidence support a benign effect (MetaRNN=0.028407544).
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SNRNP200NM_014014.5 linkuse as main transcriptc.6295A>G p.Thr2099Ala missense_variant 45/45 ENST00000323853.10 NP_054733.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SNRNP200ENST00000323853.10 linkuse as main transcriptc.6295A>G p.Thr2099Ala missense_variant 45/451 NM_014014.5 ENSP00000317123 P1O75643-1
SNRNP200ENST00000497539.5 linkuse as main transcriptn.2269A>G non_coding_transcript_exon_variant 15/151
SNRNP200ENST00000429650.1 linkuse as main transcriptn.2526A>G non_coding_transcript_exon_variant 17/172

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251374
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.000431
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.000338
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000217
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 14, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2099 of the SNRNP200 protein (p.Thr2099Ala). This variant is present in population databases (rs140574531, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SNRNP200-related conditions. ClinVar contains an entry for this variant (Variation ID: 1035929). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SNRNP200 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
19
DANN
Benign
0.86
DEOGEN2
Benign
0.061
T
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.028
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.81
N
MutationTaster
Benign
0.99
D;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
0.18
N
REVEL
Benign
0.10
Sift
Benign
0.70
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.083
MVP
0.21
MPC
0.94
ClinPred
0.073
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140574531; hg19: chr2-96940866; API