9-120974762-G-C

Variant names:

• chr9-120974762-G-C
• rs2269067
• NM_001735.3:c.4017+17C>G

Variant summary

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

The NM_001735.3(C5):​c.4017+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,602,582 control chromosomes in the GnomAD database, including 41,761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9148 hom., cov: 32)
  • Exomes 𝑓: 0.20 (32613 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.465
• Publications: 27 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=-0.85).
• BP6: Variant 9-120974762-G-C is Benign according to our data. Variant chr9-120974762-G-C is described in ClinVar as Benign. ClinVar VariationId is 1166860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001735.3. 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.4017+17C>G		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.4035+17C>G		intron	N/A	NP_001304092.1	A0A8Q3SID6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.4017+17C>G		intron	N/A	ENSP00000223642.1	P01031
	C5	ENST00000696281.1		c.4035+17C>G		intron	N/A	ENSP00000512521.1	A0A8Q3SID6
	C5	ENST00000867873.1		c.4017+17C>G		intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44933 AN: 151936 Hom.: 9119 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.203 AC: 50935 AN: 251358 AF XY: 0.193

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.198 AC: 287559 AN: 1450528 Hom.: 32613 Cov.: 30 AF XY: 0.195 AC XY: 140863 AN XY: 722452

African (AFR) AF: 0.600 AC: 19802 AN: 33028

American (AMR) AF: 0.132 AC: 5900 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3464 AN: 26078

East Asian (EAS) AF: 0.245 AC: 9692 AN: 39606

South Asian (SAS) AF: 0.124 AC: 10699 AN: 86090

European-Finnish (FIN) AF: 0.165 AC: 8816 AN: 53394

Middle Eastern (MID) AF: 0.140 AC: 803 AN: 5748

European-Non Finnish (NFE) AF: 0.196 AC: 215955 AN: 1101864

Other (OTH) AF: 0.207 AC: 12428 AN: 60016

GnomAD4 genome AF: 0.296 AC: 45011 AN: 152054 Hom.: 9148 Cov.: 32 AF XY: 0.288 AC XY: 21395 AN XY: 74352

African (AFR) AF: 0.582 AC: 24093 AN: 41430

American (AMR) AF: 0.170 AC: 2605 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1257 AN: 5174

South Asian (SAS) AF: 0.133 AC: 643 AN: 4820

European-Finnish (FIN) AF: 0.155 AC: 1637 AN: 10570

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13537 AN: 67990

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.230 Hom.: 1034

Bravo AF: 0.310

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.36
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2269067; hg19: chr9-123737040; COSMIC: COSV56326625; COSMIC: COSV56326625;