rs7746553

Variant names:

• chr6-31928196-C-G
• rs7746553
• NM_000063.6:c.256+32C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282458.2(C2):​c.169+4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,576,610 control chromosomes in the GnomAD database, including 25,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3300 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22070 hom.)
• Consequence: C2 NM_001282458.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007353
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 43 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]

C2 Gene-Disease associations (from GenCC):

• complement component 2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000244255 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282458.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.256+32C>G		intron	N/A	NP_000054.2
	C2	NM_001282458.2		c.169+4C>G		splice_region intron	N/A	NP_001269387.1	A0A0G2JL69
	C2	NM_001145903.3		c.46+398C>G		intron	N/A	NP_001139375.1	P06681-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	ENST00000299367.10	TSL:1 MANE Select	c.256+32C>G		intron	N/A	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.256+32C>G		intron	N/A	ENSP00000410815.1	B4E1Z4
	C2	ENST00000418949.6	TSL:1	c.256+32C>G		intron	N/A	ENSP00000406190.2	Q8N6L6

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30070 AN: 152044 Hom.: 3303 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.184 AC: 35810 AN: 194252 AF XY: 0.193

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.166 AC: 236332 AN: 1424448 Hom.: 22070 Cov.: 29 AF XY: 0.170 AC XY: 120126 AN XY: 707328

African (AFR) AF: 0.280 AC: 9220 AN: 32952

American (AMR) AF: 0.108 AC: 4457 AN: 41134

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3082 AN: 25630

East Asian (EAS) AF: 0.120 AC: 4651 AN: 38614

South Asian (SAS) AF: 0.320 AC: 26677 AN: 83438

European-Finnish (FIN) AF: 0.221 AC: 8954 AN: 40584

Middle Eastern (MID) AF: 0.147 AC: 843 AN: 5736

European-Non Finnish (NFE) AF: 0.153 AC: 167664 AN: 1097022

Other (OTH) AF: 0.182 AC: 10784 AN: 59338

GnomAD4 genome AF: 0.198 AC: 30103 AN: 152162 Hom.: 3300 Cov.: 32 AF XY: 0.202 AC XY: 14998 AN XY: 74380

African (AFR) AF: 0.274 AC: 11380 AN: 41496

American (AMR) AF: 0.131 AC: 2006 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3472

East Asian (EAS) AF: 0.154 AC: 797 AN: 5176

South Asian (SAS) AF: 0.326 AC: 1574 AN: 4826

European-Finnish (FIN) AF: 0.230 AC: 2442 AN: 10602

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10768 AN: 67980

Other (OTH) AF: 0.199 AC: 420 AN: 2112

Alfa AF: 0.164 Hom.: 1366

Bravo AF: 0.191

Asia WGS AF: 0.338 AC: 1173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.56
PhyloP100		-0.0090
PromoterAI		0.0072	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0060
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: rs7746553; hg19: chr6-31895973;