rs9332736

chr6-31934288-ATGGTGGACAGGGTCAGGAATCAGGAGTC-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_000063.6(C2):c.841_849+19del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. The variant allele was found at a frequency of 0.00574 in 1,612,668 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (35 hom.)
• Consequence: C2 NM_000063.6 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:1
• Conservation: PhyloP100: 4.80

Genes affected

C2 (HGNC:1248): (complement C2) Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 6-31934288-ATGGTGGACAGGGTCAGGAATCAGGAGTC-A is Pathogenic according to our data. Variant chr6-31934288-ATGGTGGACAGGGTCAGGAATCAGGAGTC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50634.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr6-31934288-ATGGTGGACAGGGTCAGGAATCAGGAGTC-A is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2	NM_000063.6	c.841_849+19del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/18	ENST00000299367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2	ENST00000299367.10	c.841_849+19del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/18	1	NM_000063.6	P1

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 772 AN: 152150 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00751

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00460 AC: 1155 AN: 251134 Hom.: 2 AF XY: 0.00424 AC XY: 576 AN XY: 135738

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00509

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00581 AC: 8479 AN: 1460400 Hom.: 35 AF XY: 0.00574 AC XY: 4172 AN XY: 726560

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00528

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152268 Hom.: 5 Cov.: 32 AF XY: 0.00484 AC XY: 360 AN XY: 74450

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00594

Gnomad4 NFE AF: 0.00751

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00847 Hom.: 2

Bravo AF: 0.00478

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00541

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	C2: PVS1, PM3, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This variant results in the deletion of part of exon 6 (c.841_849+19del) of the C2 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs572361305, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with C2 deficiency (PMID: 1577763, 9616367, 31440263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 50634). Studies have shown that this variant results in skipping of exon 6 and introduces a premature termination codon (PMID: 1577763). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2022	Functional studies demonstrate that this variant results in skipping of exon 6 (Johnson et al., 1992); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 1577763, 31440263, 25454804, 33726816, 27535533) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 23, 2022	- -

Complement component 2 deficiency Pathogenic:4 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 12, 2017	The c.841_849+19del variant in C2 is the most common pathogenic variant for C2 deficiency (Johnson 1992, Truedsson 1993), accounting for about 90% of cases (Truedsson 2015). It has been identified in 1.2% (123/10162) of Ashkenazi Jewish chromosomes and 0.8% (1001/126816) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs572361305); however, this frequency is low enough to be consistent with the frequency of C2 deficiency in the general population. This variant is a deletion of 28 bp, including the invariant region of the splice consensus sequence, and has been shown to cause skipping of exon 6, leading to a frameshift (Johnson 1992). In summary, the c.841_849+19del meets criteria to be classified as pathogenic for C2 deficiency in an autosomal recessive manner. -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Nov 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001282459.1:c.841_868del in the C2 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant also known as NM_000063.6(C2):c.841_849+19del has been reported in homozygosity in 6 probands with C2-deficiency, and segregated with disease in 2 affected homozygous relatives in one family (PMID: 1577763). The 28bp deletion leads to skipping of exon 6 and a premature stop-codon. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3, PP4, PP1. -

C2-related disorder Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 09, 2023	The C2 c.841_849+19del28 variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to result in a deletion encompassing the splice donor site at the exon 6/intron 6 boundary and has been reported to result in exon 6 skipping, with splicing prediction programs also indicating splicing alterations (Johnson et al. 1992. PubMed ID: 1577763; Alamut Visual Plus v1.6.1). This variant has been reported in many homozygous and compound heterozygous individuals with complement C2 deficiency (Zhu et al. 1998. PubMed ID: 9670930; Johnson et al. 1992. PubMed ID: 1577763; Liphaus et al. 2015. PubMed ID: 26017655; Blazina et al. 2018. PubMed ID: 29619023). Of note, heterozygous carriers of the c.841_849+19del were also found to have clinical features of C2 deficiency, including purulent meningitis, recurrent sinusitis, recurrent impetigo, pneumonia, and recurrent otitis (Blazina et al. 2018. PubMed ID: 29619023). This variant is reported in 1.18% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, the allele balance is skewed for many heterozygous individuals indicating this data may not be reliable. In the ClinVar database, this variant has been reported as pathogenic or likely pathogenic by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/50634/). Of note, alternative transcripts have been reported for the C2 gene including two which have alternative splicing omitting exon 6 (NM_001178063.2 and NM_001282457.1; Cheng and Volanakis. 1994. PubMed ID: 8120386). Taken together, we interpret this variant as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2023	Variant summary: C2 c.841_849+19del28 involves the deletion of a canonical 5' donor splice-site and is therefore predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Accordingly, several computational tools predict a significant impact on normal splicing, with three predicting the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in the skipping of exon 6, which causes a frameshift and premature termination codon that is expected to be affected by nonsense mediate decay. The variant allele was found at a frequency of 0.0046 in 251134 control chromosomes in the gnomAD database, including 2 homozygotes and is found at a high frequency (0.011) in the Ashkenazi Jewish subpopulation, providing supporting evidence for a benign role. However, c.841_849+19del28 has been reported in the literature in multiple homozygous individuals affected with Complement Component 2 Deficiency and has been found to segregate with the disease phenotype in more than one family (e.g. Johnson_1992, Rice_2016, Morup_2022). These data indicate that the variant is very likely to be associated with disease, but may exhibit reduced penetrance. The following publications have been ascertained in the context of this evaluation (PMID: 1577763, 27943079, 35874679). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=9)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

C2 deficiency, type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 05, 1992

- -

Complement component 2 deficiency;C3809653:Age related macular degeneration 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9332736; hg19: chr6-31902065;