rs10985126

Positions:

• chr9-121021656-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 402457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-121021656-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.1155A>G	p.Gly385Gly	synonymous_variant	11/41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.1173A>G	p.Gly391Gly	synonymous_variant	11/41		NP_001304092.1
C5	NM_001317164.2	c.1155A>G	p.Gly385Gly	synonymous_variant	11/21		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.1155A>G	p.Gly385Gly	synonymous_variant	11/41	1	NM_001735.3	ENSP00000223642.1

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

GnomAD3 exomes AF: 0.176 AC: 44324 AN: 251482 Hom.: 4784 AF XY: 0.170 AC XY: 23109 AN XY: 135914

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 SAS exome AF: 0.113

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

Gnomad4 AFR exome AF: 0.403

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.185

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

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.190

Alfa AF: 0.191 Hom.: 6013

Bravo AF: 0.236

Asia WGS AF: 0.225 AC: 782 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.8
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs10985126; hg19: chr9-123783934; COSMIC: COSV56324614; COSMIC: COSV56324614;