rs10985112

Variant names:

• chr9-120969130-G-A
• rs10985112
• NM_001735.3:c.4163-12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001317163.2(C5):​c.4181-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 1,610,404 control chromosomes in the GnomAD database, including 13,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4888 hom., cov: 32)
  • Exomes 𝑓: 0.085 (8437 hom.)
• Consequence: C5 NM_001317163.2 intron
• Scores: Splicing: ADA: 0.000006167
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.137
• Publications: 19 publications found

Genes affected

C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

C5 Gene-Disease associations (from GenCC):

• complement component 5 deficiency

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-120969130-G-A is Benign according to our data. Variant chr9-120969130-G-A is described in ClinVar as Benign. ClinVar VariationId is 402453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317163.2. 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
	C5	NM_001735.3	MANE Select	c.4163-12C>T		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.4181-12C>T		intron	N/A	NP_001304092.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.4163-12C>T		intron	N/A	ENSP00000223642.1
	C5	ENST00000696281.1		c.4181-12C>T		intron	N/A	ENSP00000512521.1
	C5	ENST00000867873.1		c.4163-12C>T		intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27330 AN: 152048 Hom.: 4861 Cov.: 32

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.0888

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.0977 AC: 24539 AN: 251100 AF XY: 0.0905

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.0907

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.0446

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0779

Gnomad OTH exome AF: 0.0821

GnomAD4 exome AF: 0.0846 AC: 123347 AN: 1458238 Hom.: 8437 Cov.: 29 AF XY: 0.0833 AC XY: 60417 AN XY: 725608

African (AFR) AF: 0.474 AC: 15784 AN: 33306

American (AMR) AF: 0.0926 AC: 4140 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 1692 AN: 26108

East Asian (EAS) AF: 0.0281 AC: 1114 AN: 39674

South Asian (SAS) AF: 0.0818 AC: 7048 AN: 86174

European-Finnish (FIN) AF: 0.0174 AC: 929 AN: 53402

Middle Eastern (MID) AF: 0.0912 AC: 525 AN: 5758

European-Non Finnish (NFE) AF: 0.0777 AC: 86110 AN: 1108824

Other (OTH) AF: 0.0996 AC: 6005 AN: 60270

GnomAD4 genome AF: 0.180 AC: 27405 AN: 152166 Hom.: 4888 Cov.: 32 AF XY: 0.174 AC XY: 12947 AN XY: 74408

African (AFR) AF: 0.463 AC: 19193 AN: 41448

American (AMR) AF: 0.112 AC: 1710 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.0396 AC: 205 AN: 5172

South Asian (SAS) AF: 0.0876 AC: 423 AN: 4828

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10610

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0752 AC: 5114 AN: 68020

Other (OTH) AF: 0.142 AC: 299 AN: 2112

Alfa AF: 0.107 Hom.: 7108

Bravo AF: 0.199

Asia WGS AF: 0.104 AC: 363 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.24
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000062
dbscSNV1_RF	Benign	0.0
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: rs10985112; hg19: chr9-123731408;