rs866130958

Variant names:

• chr6-31937432-C-T
• rs866130958
• NM_000063.6:c.1102C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000063.6(C2):​c.1102C>T​(p.Arg368*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: C2 NM_000063.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

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]

ENSG00000244255 (HGNC:):

C2-AS1 (HGNC:49464): (C2 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-31937432-C-T is Pathogenic according to our data. Variant chr6-31937432-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 591016.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000063.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.1102C>T	p.Arg368*	stop_gained	Exon 8 of 18	NP_000054.2
	C2	NM_001282458.2		c.1015C>T	p.Arg339*	stop_gained	Exon 8 of 18	NP_001269387.1
	C2	NM_001145903.3		c.706C>T	p.Arg236*	stop_gained	Exon 6 of 16	NP_001139375.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	ENST00000299367.10	TSL:1 MANE Select	c.1102C>T	p.Arg368*	stop_gained	Exon 8 of 18	ENSP00000299367.5
	ENSG00000244255	ENST00000456570.5	TSL:2	c.643C>T	p.Arg215*	stop_gained	Exon 5 of 30	ENSP00000410815.1
	ENSG00000244255	ENST00000477310.1	TSL:5	c.556C>T	p.Arg186*	stop_gained	Exon 4 of 28	ENSP00000418996.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460764 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000496 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.69	D
PhyloP100		1.2
Vest4		0.36
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=14/186	disease causing (fs/PTC)

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: rs866130958; hg19: chr6-31905209;