2-96287959-C-T

Position:

chr2-96287959-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1PM5PP2PP3_StrongPP5BS1_SupportingBS2

The NM_014014.5(SNRNP200):c.3269G>A(p.Arg1090Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1090L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SNRNP200
NM_014014.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.66

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]

SNRNP200 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a helix (size 26) in uniprot entity U520_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_014014.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-96287959-C-A is described in Lovd as [Likely_pathogenic].

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). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. GenCC has associacion of the gene with retinitis pigmentosa 33, SNRNP200-related dominant retinopathy, retinitis pigmentosa.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 2-96287959-C-T is Pathogenic according to our data. Variant chr2-96287959-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1360981.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr2-96287959-C-T is described in Lovd as [Pathogenic]. Variant chr2-96287959-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000219 (32/1461864) while in subpopulation EAS AF= 0.0000504 (2/39698). AF 95% confidence interval is 0.0000183. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRNP200	NM_014014.5 link	c.3269G>A	p.Arg1090Gln	missense_variant	25/45	ENST00000323853.10	NP_054733.2	O75643-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SNRNP200	ENST00000323853.10 link	c.3269G>A	p.Arg1090Gln	missense_variant	25/45	1	NM_014014.5	ENSP00000317123.5	O75643-1
SNRNP200	ENST00000652267.1 link	c.3269G>A	p.Arg1090Gln	missense_variant	27/32			ENSP00000498933.1	A0A494C1A5
SNRNP200	ENST00000480615.1 link	n.386G>A		non_coding_transcript_exon_variant	5/10	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251470

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1360981). This missense change has been observed in individual(s) with autosomal recessive inherited retinal dystrophy (PMID: 29320387). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397514574, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1090 of the SNRNP200 protein (p.Arg1090Gln). -

Retinitis pigmentosa 33

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pangenia Genomics, Pangenia Inc.

Jan 14, 2022

The SNRNP200, c.3269G>A (p.Arg1090Gln) variant is at extremely low frequency in population databases ; allele frequency in East Asia population is 0.0001 by gnomAD v2.1.1. This missense variant results in the amino acid change of p.Arg1090Gln . Another variant resulting in the amino acid change at the same position to a different residue (p.Arg1090Leu ) has been determined to be pathogenic [PMID: 19710410]. In a 4-generation Chinese family with 12 members affected by autosomal dominant retinitis pigmentosa (RP), the heterozygous variant segregated with the disease and was not found in 100 ethnically matched controls. Multiple lines of computational evidence support a deleterious effect on the gene or gene product REVEL=0. 838. There is co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. This variant has also been detected in a consanguineous Pakistani family [PMID: 29320387 ], co-segregating with an autosomal recessive form of retinitis pigmentosa. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.4

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.95

Loss of MoRF binding (P = 0.0179);

MVP

0.89

MPC

2.3

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.96

gMVP

0.89

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over