9-121074757-CA-C

Variant names:

• chr9-121074757-CA-C
• rs1362872776
• NM_001317163.2:c.79delT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001317163.2(C5):​c.79delT​(p.Cys27AlafsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 301,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: C5 NM_001317163.2 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.48
• Publications: 0 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]

CNTRL (HGNC:1858): (centriolin) This gene encodes a centrosomal protein required for the centrosome to function as a microtubule organizing center. The gene product is also associated with centrosome maturation. One version of stem cell myeloproliferative disorder is the result of a reciprocal translocation between chromosomes 8 and 9, with the breakpoint associated with fibroblast growth factor receptor 1 and centrosomal protein 1. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-121074757-CA-C is Pathogenic according to our data. Variant chr9-121074757-CA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1049860.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317163.2. 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_001317163.2		c.79delT	p.Cys27AlafsTer20	frameshift	Exon 1 of 41	NP_001304092.1	A0A8Q3SID6
	CNTRL	NM_007018.6	MANE Select	c.-514delA		upstream_gene	N/A	NP_008949.4
	CNTRL	NM_001369893.1		c.-341delA		upstream_gene	N/A	NP_001356822.1	Q5JVD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000696281.1		c.79delT	p.Cys27AlafsTer20	frameshift	Exon 1 of 42	ENSP00000512521.1	A0A8Q3SID6
	CNTRL	ENST00000690496.1		n.-513delA		non_coding_transcript_exon	Exon 1 of 18	ENSP00000508719.1	A0A8I5QL39
	C5	ENST00000696279.1		n.40delT		non_coding_transcript_exon	Exon 1 of 43	ENSP00000512520.1	A0A8Q3SIH6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000785 AC: 1 AN: 127400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000332 AC: 1 AN: 301028 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 171520

African (AFR) AF: 0.00 AC: 0 AN: 8522

American (AMR) AF: 0.00 AC: 0 AN: 27156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10696

East Asian (EAS) AF: 0.00 AC: 0 AN: 9202

South Asian (SAS) AF: 0.00 AC: 0 AN: 59496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1272

European-Non Finnish (NFE) AF: 0.00000631 AC: 1 AN: 158366

Other (OTH) AF: 0.00 AC: 0 AN: 14032

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1362872776; hg19: chr9-123837035;