rs966341758

Variant names:

• chr5-41181408-A-C
• rs966341758
• NM_000065.5:c.878T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000065.5(C6):​c.878T>G​(p.Ile293Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I293I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: C6 NM_000065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0310
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0822998).

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.878T>G	p.Ile293Ser	missense	Exon 7 of 18	NP_000056.2	P13671
	C6	NM_001115131.4		c.878T>G	p.Ile293Ser	missense	Exon 7 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.878T>G	p.Ile293Ser	missense	Exon 7 of 18	ENSP00000338861.5	P13671
	C6	ENST00000263413.7	TSL:1	c.878T>G	p.Ile293Ser	missense	Exon 7 of 18	ENSP00000263413.3	P13671
	C6	ENST00000905250.1		c.878T>G	p.Ile293Ser	missense	Exon 7 of 19	ENSP00000575309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461560 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.029
DANN	Benign	0.34
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.031
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.16
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Polyphen		0.0080	B
Vest4		0.087
MutPred		0.53		Loss of stability (P = 0.0641)
MVP		0.15
MPC		0.045
ClinPred		0.056	T
GERP RS		-3.7
Varity_R		0.081
gMVP		0.43
Mutation Taster		=91/9	polymorphism

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: rs966341758; hg19: chr5-41181510;