20-2467306-C-G

Position:

• chr20-2467306-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000381342.7(SNRPB):​c.155+301G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNRPB ENST00000381342.7 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.728

Genes affected

SNRPB (HGNC:11153): (small nuclear ribonucleoprotein polypeptides B and B1) The protein encoded by this gene is one of several nuclear proteins that are found in common among U1, U2, U4/U6, and U5 small ribonucleoprotein particles (snRNPs). These snRNPs are involved in pre-mRNA splicing, and the encoded protein may also play a role in pre-mRNA splicing or snRNP structure. Autoantibodies from patients with systemic lupus erythematosus frequently recognize epitopes on the encoded protein. Two transcript variants encoding different isoforms (B and B') have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-2467306-C-G is Pathogenic according to our data. Variant chr20-2467306-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 183431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-2467306-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRPB	NM_003091.4	c.155+301G>C		intron_variant		ENST00000381342.7	NP_003082.1
SNRPB	NM_198216.2	c.155+301G>C		intron_variant			NP_937859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNRPB	ENST00000381342.7	c.155+301G>C		intron_variant		1	NM_003091.4	ENSP00000370746	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebro-costo-mandibular syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 21, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Jan 13, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jun 16, 2020	The c.155+301G>C variant in the SNRPB gene has been previously reported in 10 unrelated individuals with cerebro-costo-mandibular syndrome(identified de novo in 6 of those individuals)and co-segregated with disease in 1 affected relative (Bacrot et al., 2015; Lynch et al., 2014; Tooley et al., 2016). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).Functional studies ofthe c.155+301G>C variant demonstrated an increased level of regulatory transcript and decreased levels of functional transcript in patient cells(Bacrot et al., 2015; Lynch et al., 2014).This variant is located in the alternate exon in the regulatory PTC transcript of SNRPB. Other pathogenic and likely pathogenic variants have been described in this exon and lead to increased transcription of the regulatory PTC transcript and decreased transcription of the functional protein coding transcripts. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.155+301G>C variant as pathogenic for autosomal dominant cerebro-costo-mandibular syndrome based on the information above.[ACMG evidence codes used: PS3_Supporting; PM1; PM2; PM6_VeryStrong] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with cerebrocostomandibular syndrome (MIM#117650). Pathogenic variants cluster at two conserved exonic splicing silencer regulatory sites in a premature termination codon (PTC) containing alternative exon, which undergoes nonsense-mediated decay and serves to regulate expression of the functional transcripts. Pathogenic variants promote the inclusion of the PTC-containing alternative exon, resulting in reduced expression of the functional transcripts (PMID: 25047197, 25504470, 26971886). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant with known effect. This intronic variant also results in a missense variant in a regulatory exon of the alternative PTC-containing transcript (ENST00000474384:c.165G>C; p.(Arg55Ser)). This alternative transcript is important for regulation of SNRPB expression, a gene that encodes core components of major spliceosome subunits. The variant results in increased expression of the PTC-containing transcript, inclusion of an alternative exon, and an overall decrease in total SNRPB expression (PMID: 25047197). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - Alternative nucleotide changes at the same intronic position have been observed in gnomAD (v2 & v3) (highest allele count: 16 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with cerebrocostomandibular syndrome (MIM#117650), many of whom were de novo, and is often annotated as g.2447952C>G (GRCh37) using the genomic location (ClinVar, LOVD, PMID: 25047197, PMID: 26971886). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 25504470, 25047197, 26971886, 26240113, 35982159, 37161864, 33057194) -

SNRPB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

The SNRPB c.155+301G>C variant is predicted to interfere with splicing. This variant has frequently been reported to occur de novo in patients with Cerebro-costo-mandibular syndrome (CCMS) (Lynch et al 2014. PubMed ID: 25047197; Patient 2, Supplemental Table S1, Bacrot et al 2014. PubMed ID: 25504470; Table 2, Tooley et al 2016. PubMed ID: 26971886). This variant results in the inclusion of a regulatory exon that triggers nonsense-mediated mRNA decay of the transcript (Lynch et al 2014. PubMed ID: 25047197). Prenatal presentations of CCMS can include increased nuchal translucency, intrauterine growth retardation, polyhydraminos, and micrognathia (Tooley et al 2016. PubMed ID: 26971886). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

Other links and lift over

dbSNP: rs786201019; hg19: chr20-2447952;