rs41258306

Positions:

• chr9-120953825-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.4806A>G​(p.Lys1602=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 1,613,206 control chromosomes in the GnomAD database, including 3,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (308 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3360 hom.)
• Consequence: C5 NM_001735.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0580

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=-0.69).
• BP6: Variant 9-120953825-T-C is Benign according to our data. Variant chr9-120953825-T-C is described in ClinVar as [Benign]. Clinvar id is 402450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.4806A>G	p.Lys1602=	synonymous_variant	40/41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.4824A>G	p.Lys1608=	synonymous_variant	40/41		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.4806A>G	p.Lys1602=	synonymous_variant	40/41	1	NM_001735.3	ENSP00000223642	P1

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8825 AN: 152190 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0650

Gnomad OTH AF: 0.0570

GnomAD3 exomes AF: 0.0571 AC: 14348 AN: 251378 Hom.: 506 AF XY: 0.0572 AC XY: 7776 AN XY: 135860

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.0599

Gnomad ASJ exome AF: 0.0648

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.0676

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0686

Gnomad OTH exome AF: 0.0584

GnomAD4 exome AF: 0.0643 AC: 93873 AN: 1460898 Hom.: 3360 Cov.: 31 AF XY: 0.0645 AC XY: 46892 AN XY: 726806

Gnomad4 AFR exome AF: 0.0652

Gnomad4 AMR exome AF: 0.0592

Gnomad4 ASJ exome AF: 0.0620

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0678

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0635

GnomAD4 genome AF: 0.0581 AC: 8842 AN: 152308 Hom.: 308 Cov.: 32 AF XY: 0.0559 AC XY: 4160 AN XY: 74484

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.0592

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0736

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0650

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0673 Hom.: 450

Bravo AF: 0.0616

Asia WGS AF: 0.0420 AC: 147 AN: 3478

EpiCase AF: 0.0703

EpiControl AF: 0.0713

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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	-0.69
CADD	Benign	2.0
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs41258306; hg19: chr9-123716103;