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rs1042663

chr6-31937353-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000063.6(C2):c.1023G>A(p.Ala341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0996 in 1,612,312 control chromosomes in the GnomAD database, including 8,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1220 hom., cov: 29)
Exomes 𝑓: 0.098 ( 7765 hom. )

Consequence

C2
NM_000063.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0410
Variant links:
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]
C2-AS1 (HGNC:49464): (C2 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-31937353-G-A is Benign according to our data. Variant chr6-31937353-G-A is described in ClinVar as [Benign]. Clinvar id is 356245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31937353-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.041 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
C2NM_000063.6 linkuse as main transcriptc.1023G>A p.Ala341= synonymous_variant 8/18 ENST00000299367.10
C2-AS1NR_104191.1 linkuse as main transcriptn.541-1951C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
C2ENST00000299367.10 linkuse as main transcriptc.1023G>A p.Ala341= synonymous_variant 8/181 NM_000063.6 P1P06681-1
C2-AS1ENST00000630806.1 linkuse as main transcriptn.541-1951C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.117
AC:
17727
AN:
151746
Hom.:
1222
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.191
Gnomad AMI
AF:
0.0462
Gnomad AMR
AF:
0.101
Gnomad ASJ
AF:
0.0574
Gnomad EAS
AF:
0.0589
Gnomad SAS
AF:
0.142
Gnomad FIN
AF:
0.0577
Gnomad MID
AF:
0.0886
Gnomad NFE
AF:
0.0908
Gnomad OTH
AF:
0.131
GnomAD3 exomes
AF:
0.0969
AC:
23910
AN:
246640
Hom.:
1391
AF XY:
0.0999
AC XY:
13434
AN XY:
134446
show subpopulations
Gnomad AFR exome
AF:
0.191
Gnomad AMR exome
AF:
0.0704
Gnomad ASJ exome
AF:
0.0522
Gnomad EAS exome
AF:
0.0591
Gnomad SAS exome
AF:
0.162
Gnomad FIN exome
AF:
0.0636
Gnomad NFE exome
AF:
0.0908
Gnomad OTH exome
AF:
0.103
GnomAD4 exome
AF:
0.0978
AC:
142895
AN:
1460448
Hom.:
7765
Cov.:
33
AF XY:
0.0989
AC XY:
71870
AN XY:
726556
show subpopulations
Gnomad4 AFR exome
AF:
0.188
Gnomad4 AMR exome
AF:
0.0739
Gnomad4 ASJ exome
AF:
0.0555
Gnomad4 EAS exome
AF:
0.0713
Gnomad4 SAS exome
AF:
0.156
Gnomad4 FIN exome
AF:
0.0651
Gnomad4 NFE exome
AF:
0.0946
Gnomad4 OTH exome
AF:
0.109
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.117
AC:
17747
AN:
151864
Hom.:
1220
Cov.:
29
AF XY:
0.115
AC XY:
8509
AN XY:
74238
show subpopulations
Gnomad4 AFR
AF:
0.191
Gnomad4 AMR
AF:
0.100
Gnomad4 ASJ
AF:
0.0574
Gnomad4 EAS
AF:
0.0589
Gnomad4 SAS
AF:
0.141
Gnomad4 FIN
AF:
0.0577
Gnomad4 NFE
AF:
0.0908
Gnomad4 OTH
AF:
0.130
Alfa
AF:
0.0920
Hom.:
1604
Bravo
AF:
0.123
Asia WGS
AF:
0.155
AC:
536
AN:
3478
EpiCase
AF:
0.0869
EpiControl
AF:
0.0884

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Complement component 2 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Age related macular degeneration 14 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
Cadd
Benign
9.5
Dann
Benign
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1042663; hg19: chr6-31905130; API