rs9332730

Variant names:

• chr6-31944232-G-C
• rs9332730
• NM_000063.6:c.1902+6G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-31944232-G-C
• chr6-31944232-G-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000063.6(C2):​c.1902+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,595,440 control chromosomes in the GnomAD database, including 2,913 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (282 hom., cov: 31)
  • Exomes 𝑓: 0.050 (2631 hom.)
• Consequence: C2 NM_000063.6 splice_region, intron
• Scores: Splicing: ADA: 0.0006264
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00800
• Publications: 23 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-31944232-G-C is Benign according to our data. Variant chr6-31944232-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.1902+6G>C		splice_region intron	N/A	NP_000054.2
	C2	NM_001282458.2		c.1815+6G>C		splice_region intron	N/A	NP_001269387.1	A0A0G2JL69
	C2	NM_001145903.3		c.1506+6G>C		splice_region 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.1902+6G>C		splice_region intron	N/A	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.1443+6G>C		splice_region intron	N/A	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.1215+6G>C		splice_region intron	N/A	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 7333 AN: 152050 Hom.: 282 Cov.: 31

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0488

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0561 AC: 13833 AN: 246480 AF XY: 0.0621

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00482

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0487

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0497 AC: 71680 AN: 1443272 Hom.: 2631 Cov.: 28 AF XY: 0.0528 AC XY: 37973 AN XY: 719252

African (AFR) AF: 0.0241 AC: 800 AN: 33154

American (AMR) AF: 0.0221 AC: 987 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00968 AC: 252 AN: 26038

East Asian (EAS) AF: 0.00308 AC: 122 AN: 39616

South Asian (SAS) AF: 0.118 AC: 10145 AN: 85896

European-Finnish (FIN) AF: 0.140 AC: 7312 AN: 52274

Middle Eastern (MID) AF: 0.0782 AC: 448 AN: 5726

European-Non Finnish (NFE) AF: 0.0449 AC: 49219 AN: 1096080

Other (OTH) AF: 0.0401 AC: 2395 AN: 59782

GnomAD4 genome AF: 0.0482 AC: 7335 AN: 152168 Hom.: 282 Cov.: 31 AF XY: 0.0531 AC XY: 3953 AN XY: 74382

African (AFR) AF: 0.0266 AC: 1105 AN: 41530

American (AMR) AF: 0.0306 AC: 468 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00908 AC: 47 AN: 5174

South Asian (SAS) AF: 0.111 AC: 534 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1652 AN: 10576

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0488 AC: 3319 AN: 67990

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0422 Hom.: 47

Bravo AF: 0.0360

Asia WGS AF: 0.0360 AC: 123 AN: 3478

EpiCase AF: 0.0469

EpiControl AF: 0.0459

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Age related macular degeneration 14 (1)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Complement component 2 deficiency (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		0.0080
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.060		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: rs9332730; hg19: chr6-31912009;