rs2305060

Variant names:

• chr5-41203242-C-T
• rs2305060
• NM_000065.5:c.-12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000065.5(C6):​c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,624 control chromosomes in the GnomAD database, including 8,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (870 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7731 hom.)
• Consequence: C6 NM_000065.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.427
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-41203242-C-T is Benign according to our data. Variant chr5-41203242-C-T is described in ClinVar as Benign. ClinVar VariationId is 402459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C6	NM_000065.5	MANE Select	c.-12G>A		5_prime_UTR	Exon 2 of 18	NP_000056.2
	C6	NM_001115131.4		c.-12G>A		5_prime_UTR	Exon 2 of 18	NP_001108603.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C6	ENST00000337836.10	TSL:1 MANE Select	c.-12G>A		5_prime_UTR	Exon 2 of 18	ENSP00000338861.5
	C6	ENST00000263413.7	TSL:1	c.-12G>A		5_prime_UTR	Exon 2 of 18	ENSP00000263413.3
	C6	ENST00000706655.1		n.262G>A		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16393 AN: 152060 Hom.: 870 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.0914

GnomAD2 exomes AF: 0.101 AC: 25381 AN: 250750 AF XY: 0.101

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0843

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0875

Gnomad NFE exome AF: 0.0911

Gnomad OTH exome AF: 0.0972

GnomAD4 exome AF: 0.100 AC: 146169 AN: 1461446 Hom.: 7731 Cov.: 32 AF XY: 0.100 AC XY: 72736 AN XY: 727078

African (AFR) AF: 0.137 AC: 4572 AN: 33466

American (AMR) AF: 0.117 AC: 5249 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 2141 AN: 26126

East Asian (EAS) AF: 0.144 AC: 5733 AN: 39686

South Asian (SAS) AF: 0.114 AC: 9835 AN: 86236

European-Finnish (FIN) AF: 0.0873 AC: 4660 AN: 53392

Middle Eastern (MID) AF: 0.0964 AC: 556 AN: 5766

European-Non Finnish (NFE) AF: 0.0964 AC: 107194 AN: 1111676

Other (OTH) AF: 0.103 AC: 6229 AN: 60380

GnomAD4 genome AF: 0.108 AC: 16409 AN: 152178 Hom.: 870 Cov.: 32 AF XY: 0.108 AC XY: 8002 AN XY: 74412

African (AFR) AF: 0.139 AC: 5776 AN: 41514

American (AMR) AF: 0.106 AC: 1619 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 300 AN: 3472

East Asian (EAS) AF: 0.112 AC: 580 AN: 5180

South Asian (SAS) AF: 0.105 AC: 509 AN: 4828

European-Finnish (FIN) AF: 0.0936 AC: 991 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0928 AC: 6309 AN: 67996

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.0983 Hom.: 978

Bravo AF: 0.111

Asia WGS AF: 0.0940 AC: 327 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.35
PhyloP100		-0.43
Mutation Taster		=300/0	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: rs2305060; hg19: chr5-41203344; COSMIC: COSV54707270;