9-121021656-T-C

Variant names:

• chr9-121021656-T-C
• rs10985126
• NM_001735.3:c.1155A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001735.3(C5):​c.1155A>G​(p.Gly385Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,844 control chromosomes in the GnomAD database, including 30,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4847 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25887 hom.)
• Consequence: C5 NM_001735.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.109
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-121021656-T-C is Benign according to our data. Variant chr9-121021656-T-C is described in ClinVar as Benign. ClinVar VariationId is 402457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.109 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 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.1155A>G	p.Gly385Gly	synonymous	Exon 11 of 41	NP_001726.2
	C5	NM_001317163.2		c.1173A>G	p.Gly391Gly	synonymous	Exon 11 of 41	NP_001304092.1
	C5	NM_001317164.2		c.1155A>G	p.Gly385Gly	synonymous	Exon 11 of 21	NP_001304093.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.1155A>G	p.Gly385Gly	synonymous	Exon 11 of 41	ENSP00000223642.1
	C5	ENST00000696281.1		c.1173A>G	p.Gly391Gly	synonymous	Exon 11 of 42	ENSP00000512521.1
	C5	ENST00000867873.1		c.1155A>G	p.Gly385Gly	synonymous	Exon 11 of 40	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34914 AN: 151948 Hom.: 4845 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.176 AC: 44324 AN: 251482 AF XY: 0.170

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.243

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.180 AC: 263495 AN: 1460778 Hom.: 25887 Cov.: 32 AF XY: 0.178 AC XY: 129150 AN XY: 726820

African (AFR) AF: 0.403 AC: 13473 AN: 33456

American (AMR) AF: 0.112 AC: 4996 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3149 AN: 26132

East Asian (EAS) AF: 0.249 AC: 9873 AN: 39686

South Asian (SAS) AF: 0.114 AC: 9862 AN: 86242

European-Finnish (FIN) AF: 0.143 AC: 7636 AN: 53416

Middle Eastern (MID) AF: 0.106 AC: 611 AN: 5766

European-Non Finnish (NFE) AF: 0.182 AC: 202747 AN: 1111008

Other (OTH) AF: 0.185 AC: 11148 AN: 60348

GnomAD4 genome AF: 0.230 AC: 34956 AN: 152066 Hom.: 4847 Cov.: 32 AF XY: 0.224 AC XY: 16622 AN XY: 74332

African (AFR) AF: 0.388 AC: 16064 AN: 41448

American (AMR) AF: 0.138 AC: 2105 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3468

East Asian (EAS) AF: 0.252 AC: 1301 AN: 5164

South Asian (SAS) AF: 0.128 AC: 616 AN: 4822

European-Finnish (FIN) AF: 0.132 AC: 1394 AN: 10574

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12587 AN: 67986

Other (OTH) AF: 0.190 AC: 402 AN: 2112

Alfa AF: 0.202 Hom.: 10014

Bravo AF: 0.236

Asia WGS AF: 0.225 AC: 782 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.169

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.8
DANN	Benign	0.70
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10985126; hg19: chr9-123783934; COSMIC: COSV56324614; COSMIC: COSV56324614;