chr9-121006922-C-T

Position:

• chr9-121006922-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001735.3(C5):​c.2404G>A​(p.Val802Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,604,840 control chromosomes in the GnomAD database, including 166,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (12597 hom., cov: 32)
  • Exomes 𝑓: 0.45 (153644 hom.)
• Consequence: C5 NM_001735.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.385

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2777105E-5).
• BP6: Variant 9-121006922-C-T is Benign according to our data. Variant chr9-121006922-C-T is described in ClinVar as [Benign]. Clinvar id is 402454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-121006922-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.2404G>A	p.Val802Ile	missense_variant	19/41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2422G>A	p.Val808Ile	missense_variant	19/41		NP_001304092.1
C5	NM_001317164.2	c.2404G>A	p.Val802Ile	missense_variant	19/21		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2404G>A	p.Val802Ile	missense_variant	19/41	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55524 AN: 151940 Hom.: 12586 Cov.: 32

Gnomad AFR AF: 0.0857

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.471 AC: 118467 AN: 251326 Hom.: 30016 AF XY: 0.484 AC XY: 65709 AN XY: 135848

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.518

Gnomad EAS exome AF: 0.561

Gnomad SAS exome AF: 0.632

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.439

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.451 AC: 655711 AN: 1452782 Hom.: 153644 Cov.: 31 AF XY: 0.458 AC XY: 331393 AN XY: 723154

Gnomad4 AFR exome AF: 0.0714

Gnomad4 AMR exome AF: 0.541

Gnomad4 ASJ exome AF: 0.512

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.488

Gnomad4 NFE exome AF: 0.439

Gnomad4 OTH exome AF: 0.446

GnomAD4 genome AF: 0.365 AC: 55533 AN: 152058 Hom.: 12597 Cov.: 32 AF XY: 0.376 AC XY: 27909 AN XY: 74324

Gnomad4 AFR AF: 0.0855

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.512

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.409

Alfa AF: 0.435 Hom.: 38378

Bravo AF: 0.351

TwinsUK AF: 0.433 AC: 1606

ALSPAC AF: 0.430 AC: 1657

ESP6500AA AF: 0.0899 AC: 396

ESP6500EA AF: 0.445 AC: 3829

ExAC AF: 0.459 AC: 55672

Asia WGS AF: 0.532 AC: 1849 AN: 3476

EpiCase AF: 0.448

EpiControl AF: 0.442

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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: MAF -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.99	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.021
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		0.13	B
Vest4		0.043
MPC		0.16
ClinPred		0.0031	T
GERP RS		1.1
Varity_R		0.19
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17611; hg19: chr9-123769200; COSMIC: COSV56324110;