rs61469168

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.23

Variant links:

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]

C6 links:

LOC105374739 (HGNC:):

LOC105374739 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00301

AC:

458

AN:

152184

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000576

AC XY:

AN XY:

135386

show subpopulations

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.:

Cov.:

AF XY:

0.000261

AC XY:

187

AN XY:

715784

show subpopulations

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.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.00364

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complement component 6 deficiency

Pathogenic:6

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	Mendelics	May 04, 2022	- -
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	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	Fulgent Genetics, Fulgent Genetics	Apr 09, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 1996	- -

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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

C6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2023

The C6 c.1879delG variant is predicted to result in a frameshift and premature protein termination (p.Asp627Thrfs*4). This variant is present at a maximum allele frequency of 1.12% in Africans and is present in the homozygous state in two individuals in a large population database (http://gnomad.broadinstitute.org/variant/5-41158864-TC-T). This variant has been reported in many patients 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 reported in 1.1% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-41158864-TC-T). Frameshift variants in C6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over