chr5-41158762-TC-T

Variant names:

• chr5-41158762-TC-T
• rs61469168
• NM_000065.5:c.1879delG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_000065.5(C6):​c.1879delG​(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 has been classified as Pathogenic. 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:12
• Conservation: PhyloP100: 2.23
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• complement component 6 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000307984 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 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 VariationId is 505659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000065.5. 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
	C6	NM_000065.5	MANE Select	c.1879delG	p.Asp627ThrfsTer4	frameshift	Exon 13 of 18	NP_000056.2	P13671
	C6	NM_001115131.4		c.1879delG	p.Asp627ThrfsTer4	frameshift	Exon 13 of 18	NP_001108603.2	P13671

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C6	ENST00000337836.10	TSL:1 MANE Select	c.1879delG	p.Asp627ThrfsTer4	frameshift	Exon 13 of 18	ENSP00000338861.5	P13671
	C6	ENST00000263413.7	TSL:1	c.1879delG	p.Asp627ThrfsTer4	frameshift	Exon 13 of 18	ENSP00000263413.3	P13671
	C6	ENST00000905250.1		c.1936delG	p.Asp646ThrfsTer4	frameshift	Exon 14 of 19	ENSP00000575309.1

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

GnomAD2 exomes AF: 0.000842 AC: 211 AN: 250526 AF XY: 0.000576

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 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

African (AFR) AF: 0.0114 AC: 375 AN: 32936

American (AMR) AF: 0.000627 AC: 28 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 85738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5724

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1087914

Other (OTH) AF: 0.000572 AC: 34 AN: 59390

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

African (AFR) AF: 0.0103 AC: 430 AN: 41568

American (AMR) AF: 0.00164 AC: 25 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00364

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Complement component 6 deficiency (8)
2	-	-	not provided (2)
1	-	-	C6-related disorder (1)
1	-	-	Immunodeficiency due to a late component of complement deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61469168; hg19: chr5-41158864;