rs61469168

Positions:

• chr5-41158762-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000065.5(C6):​c.1879del​(p.Asp627ThrfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,587,380 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D627D) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: C6 NM_000065.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.23

Genes affected

C6 (HGNC:1339): (complement C6) This gene encodes a component of the complement cascade. The encoded protein is part of the membrane attack complex that can be incorporated into the cell membrane and cause cell lysis. Mutations in this gene are associated with complement component-6 deficiency. Transcript variants encoding the same protein have been described.[provided by RefSeq, Nov 2012]

LOC105374739 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-41158762-TC-T is Pathogenic according to our data. Variant chr5-41158762-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 505659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C6	NM_000065.5	c.1879del	p.Asp627ThrfsTer4	frameshift_variant	13/18	ENST00000337836.10	NP_000056.2
LOC105374739	XR_001742650.2	n.887-2550del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C6	ENST00000337836.10	c.1879del	p.Asp627ThrfsTer4	frameshift_variant	13/18	1	NM_000065.5	ENSP00000338861	P1
C6	ENST00000263413.7	c.1879del	p.Asp627ThrfsTer4	frameshift_variant	13/18	1		ENSP00000263413	P1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000842 AC: 211 AN: 250526 Hom.: 3 AF XY: 0.000576 AC XY: 78 AN XY: 135386

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000314 AC: 450 AN: 1435078 Hom.: 3 Cov.: 27 AF XY: 0.000261 AC XY: 187 AN XY: 715784

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.000572

GnomAD4 genome AF: 0.00301 AC: 459 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74458

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00364

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complement component 6 deficiency Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 22, 2021	C6 NM_000065 exon 13 p.Asp627fs (c.1879delG): This variant has been reported in the literature in at least 9 individuals with suspected C6 deficiency, segregating with disease in at least 7 affected family members as homozygous or compound heterozygous (Nishizaka 1996 PMID:8690922, Hobart 1998 PMID:9856498, Zhu 1998 PMID:9472666, Dragon-Durey 2003 PMID:12653841, reported as G1936). This variant is present in 1% (268/24026) of African alleles, including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61469168); however, this frequency is consistent with the reported incidence of disease. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of one nucleotide and creates a premature stop codon four amino acids downstream from this location which results in an absent or abnormal protein. In summary, this variant is classified as pathogenic based on the predicted impact to the protein, numerous affected probands with this variant and segregation studies. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2023	The p.Asp627ThrfsX4 variant in C6 (NM_000065.3 c.1879delG; also referred to as c.1936delG in the literature) has been reported in 4 homozygous and 7 compound heterozygous African individuals with complement component 6 deficiency and susceptibility to Neisseria infections or recurrent infections and segregated with C6 deficiency in at least 7 affected relatives from 3 families, though none of these individuals presented with a history of infections and were asymptomatic at the time of reporting (Nishizaka 1996 PMID: 8690922, Zhu 1998PMID: 9472666, Hobart PMID: 9856498, Dragon-Durey 2003 PMID: 12653841, and Orren 2012 PMID: 22288589). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 505659) and has been identified in 1.0% (429/41446) of African chromosomes by gnomAD, including 2 homozygotes (http://gnomad.broadinstitute.org, v.3.1.2), however, this frequency is consistent with the reported incidence of disease. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 627 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the C6 gene is an established disease mechanism in complement component 6 deficiency, which is associated with susceptibility to Neisseria infections, including meningitis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Complement component 6 deficiency. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2024	Variant summary: C6 c.1879delG (p.Asp627ThrfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00084 in 250526 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in C6 causing Complement Component 6 Deficiency, allowing no conclusion about variant significance. c.1879delG has been reported in the literature in multiple homozygous individuals affected with Complement Component 6 Deficiency (e.g. Dragon-Durey_2003). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 12653841). ClinVar contains an entry for this variant (Variation ID: 505659). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 23, 2022	ACMG classification criteria: PVS1 very strong, PM3 very strong, PP1 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Asp627Thrfs*4) in the C6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C6 are known to be pathogenic (PMID: 17257682). This variant is present in population databases (rs61469168, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with complement component C6 deficiency (PMID: 8690922, 12653841). This variant is also known as c.1936delG. ClinVar contains an entry for this variant (Variation ID: 505659). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as c.1936delG; This variant is associated with the following publications: (PMID: 35655932, Rizvi2023[paper], 12653841, 22344438, 30609409, 28368462, 9472666, 22288589, 10632667, 9856498, 8512929, 35717718, 30797079, 8690922) -

Immunodeficiency due to a late component of complement deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_000065.2:c.1879delG in the C6 gene has an allele frequency of 0.011 in African subpopulation in the gnomAD database. The p.Asp627Metfs*4 (c.1879delG) variant in C6 has been reported African individuals with Complement component 6 deficiency, including homozygotes and compound heterozygotes 828delG/1879delG (PMID: 9856498; 22288589). This variant is a deletion of one nucleotide and creates a premature stop codon four amino acids downstream from this location which results in an absent or abnormal protein. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3_Strong. -

C6-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The C6 c.1879delG variant is predicted to result in a frameshift and premature protein termination (p.Asp627Thrfs*4). This variant has been reported in many individuals as a cause of C6 deficiency (OMIM #612446) and is particularly common among Western Cape South Africans (aka c.1936delG; Zhu et al. 2000. PubMed ID: 10632667; Nishizaka et al. 1996. PubMed ID: 8690922; Parham et al. 2007. PubMed ID: 17257682; Orren et al. 2012. PubMed ID: 22288589). This variant is present at a maximum allele frequency of 1.12% in Africans and is present in the homozygous state in three individuals in a large population database. Frameshift variants in C6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61469168; hg19: chr5-41158864;