5-41143004-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000065.5(C6):c.2626T>C(p.Ser876Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C6 NM_000065.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0746184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C6	NM_000065.5	c.2626T>C	p.Ser876Pro	missense_variant, splice_region_variant	18/18	ENST00000337836.10
LOC105374739	XR_001742650.2	n.887-18309A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C6	ENST00000337836.10	c.2626T>C	p.Ser876Pro	missense_variant, splice_region_variant	18/18	1	NM_000065.5	P1
C6	ENST00000263413.7	c.2626T>C	p.Ser876Pro	missense_variant, splice_region_variant	18/18	1		P1
C6	ENST00000706654.1	n.793T>C		splice_region_variant, non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with C6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 876 of the C6 protein (p.Ser876Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.097	N
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.083
Sift	Benign	0.062	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0020	B;B
Vest4		0.12
MutPred		0.30		Gain of glycosylation at S878 (P = 0.0993);Gain of glycosylation at S878 (P = 0.0993);
MVP		0.72
MPC		0.040
ClinPred		0.13	T
GERP RS		-2.8
Varity_R		0.37
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-41143106;