rs700233

Positions:

• chr5-39364452-G-A
• chr5-39364452-G-T

Variant summary

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

The NM_001737.5(C9):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,600,716 control chromosomes in the GnomAD database, including 121,576 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 0.35 (9967 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111609 hom.)
• Consequence: C9 NM_001737.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.28

Genes affected

C9 (HGNC:1358): (complement C9) This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency. [provided by RefSeq, Feb 2009]

C9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7780066E-4).
• BP6: Variant 5-39364452-G-A is Benign according to our data. Variant chr5-39364452-G-A is described in ClinVar as [Benign]. Clinvar id is 402466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-39364452-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9	NM_001737.5	c.13C>T	p.Arg5Trp	missense_variant	1/11	ENST00000263408.5	NP_001728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9	ENST00000263408.5	c.13C>T	p.Arg5Trp	missense_variant	1/11	1	NM_001737.5	ENSP00000263408.4

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53587 AN: 151946 Hom.: 9971 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0706

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.360 AC: 90006 AN: 249768 Hom.: 17503 AF XY: 0.368 AC XY: 49696 AN XY: 134982

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.0552

Gnomad SAS exome AF: 0.361

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.386 AC: 559842 AN: 1448652 Hom.: 111609 Cov.: 28 AF XY: 0.388 AC XY: 279669 AN XY: 721376

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.352

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.352 AC: 53598 AN: 152064 Hom.: 9967 Cov.: 32 AF XY: 0.353 AC XY: 26204 AN XY: 74324

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.0708

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.412

Alfa AF: 0.395 Hom.: 19854

Bravo AF: 0.348

TwinsUK AF: 0.393 AC: 1459

ALSPAC AF: 0.397 AC: 1529

ESP6500AA AF: 0.254 AC: 1121

ESP6500EA AF: 0.414 AC: 3563

ExAC AF: 0.361 AC: 43802

Asia WGS AF: 0.234 AC: 819 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.435

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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: Frequency -

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	0.095
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.019
DANN	Benign	0.51
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.049
Sift	Benign	0.21	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.034
ClinPred		0.012	T
GERP RS		-8.7
Varity_R		0.031
gMVP		0.28

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: rs700233; hg19: chr5-39364554; COSMIC: COSV54676608;