rs17611

Variant names:

• chr9-121006922-C-T
• rs17611
• NM_001735.3:c.2404G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-121006922-C-T
• chr9-121006922-C-A
• chr9-121006922-C-G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 117 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 -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 VariationId is 402454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.609 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.2404G>A	p.Val802Ile	missense	Exon 19 of 41	NP_001726.2
	C5	NM_001317163.2		c.2422G>A	p.Val808Ile	missense	Exon 19 of 41	NP_001304092.1	A0A8Q3SID6
	C5	NM_001317164.2		c.2404G>A	p.Val802Ile	missense	Exon 19 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.2404G>A	p.Val802Ile	missense	Exon 19 of 41	ENSP00000223642.1	P01031
	C5	ENST00000696281.1		c.2422G>A	p.Val808Ile	missense	Exon 19 of 42	ENSP00000512521.1	A0A8Q3SID6
	C5	ENST00000867873.1		c.2404G>A	p.Val802Ile	missense	Exon 19 of 40	ENSP00000537932.1

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

GnomAD2 exomes AF: 0.471 AC: 118467 AN: 251326 AF XY: 0.484

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 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

African (AFR) AF: 0.0714 AC: 2387 AN: 33434

American (AMR) AF: 0.541 AC: 24193 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 13330 AN: 26058

East Asian (EAS) AF: 0.533 AC: 21123 AN: 39598

South Asian (SAS) AF: 0.633 AC: 54456 AN: 86016

European-Finnish (FIN) AF: 0.488 AC: 26076 AN: 53394

Middle Eastern (MID) AF: 0.507 AC: 2910 AN: 5744

European-Non Finnish (NFE) AF: 0.439 AC: 484417 AN: 1103768

Other (OTH) AF: 0.446 AC: 26819 AN: 60070

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

African (AFR) AF: 0.0855 AC: 3547 AN: 41508

American (AMR) AF: 0.491 AC: 7503 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1808 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2902 AN: 5170

South Asian (SAS) AF: 0.628 AC: 3019 AN: 4806

European-Finnish (FIN) AF: 0.512 AC: 5404 AN: 10562

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29762 AN: 67950

Other (OTH) AF: 0.409 AC: 863 AN: 2108

Alfa AF: 0.423 Hom.: 72539

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.39
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17611; hg19: chr9-123769200; COSMIC: COSV56324110;