rs4245977

Variant names:

• chr5-41195598-C-T
• rs4245977
• NM_000065.5:c.587+194G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000065.5(C6):​c.587+194G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,158 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (875 hom., cov: 32)
• Consequence: C6 NM_000065.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.659
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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.587+194G>A		intron	N/A	NP_000056.2	P13671
	C6	NM_001115131.4		c.587+194G>A		intron	N/A	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.587+194G>A		intron	N/A	ENSP00000338861.5	P13671
	C6	ENST00000263413.7	TSL:1	c.587+194G>A		intron	N/A	ENSP00000263413.3	P13671
	C6	ENST00000905250.1		c.587+194G>A		intron	N/A	ENSP00000575309.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16434 AN: 152040 Hom.: 875 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.0912

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16450 AN: 152158 Hom.: 875 Cov.: 32 AF XY: 0.108 AC XY: 8013 AN XY: 74368

African (AFR) AF: 0.140 AC: 5821 AN: 41496

American (AMR) AF: 0.107 AC: 1630 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.112 AC: 577 AN: 5172

South Asian (SAS) AF: 0.105 AC: 508 AN: 4826

European-Finnish (FIN) AF: 0.0936 AC: 992 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6299 AN: 68000

Other (OTH) AF: 0.0907 AC: 191 AN: 2106

Alfa AF: 0.0986 Hom.: 1241

Bravo AF: 0.111

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4245977; hg19: chr5-41195700; COSMIC: COSV54718776; COSMIC: COSV54718776;