rs9332457

Variant names:

• chr5-41185070-C-A
• rs9332457
• NM_000065.5:c.726+1000G>T

Variant summary

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

The NM_000065.5(C6):​c.726+1000G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,950 control chromosomes in the GnomAD database, including 13,704 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 0.42 (13704 hom., cov: 32)
• Consequence: C6 NM_000065.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C6	NM_000065.5	c.726+1000G>T		intron_variant	Intron 6 of 17	ENST00000337836.10	NP_000056.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C6	ENST00000337836.10	c.726+1000G>T		intron_variant	Intron 6 of 17	1	NM_000065.5	ENSP00000338861.5
C6	ENST00000263413.7	c.726+1000G>T		intron_variant	Intron 6 of 17	1		ENSP00000263413.3
C6	ENST00000475349.5	n.125+1197G>T		intron_variant	Intron 1 of 5	3
C6	ENST00000706655.1	n.999+1000G>T		intron_variant	Intron 6 of 10

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63803 AN: 151830 Hom.: 13696 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.420 AC: 63849 AN: 151950 Hom.: 13704 Cov.: 32 AF XY: 0.417 AC XY: 30970 AN XY: 74244

African (AFR) AF: 0.455 AC: 18835 AN: 41438

American (AMR) AF: 0.327 AC: 5000 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1098 AN: 3468

East Asian (EAS) AF: 0.128 AC: 665 AN: 5180

South Asian (SAS) AF: 0.301 AC: 1449 AN: 4810

European-Finnish (FIN) AF: 0.479 AC: 5043 AN: 10534

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.447 AC: 30371 AN: 67932

Other (OTH) AF: 0.419 AC: 885 AN: 2112

Alfa AF: 0.428 Hom.: 7667

Bravo AF: 0.405

Asia WGS AF: 0.215 AC: 746 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.49
PhyloP100		-0.53
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: rs9332457; hg19: chr5-41185172; COSMIC: COSV54712701;