rs1801033

Variant names:

• chr5-41199857-G-T
• rs1801033
• NM_000065.5:c.356C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-41199857-G-T
• chr5-41199857-G-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.356C>A​(p.Ala119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,612,364 control chromosomes in the GnomAD database, including 311,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A119A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.60 (27570 hom., cov: 32)
  • Exomes 𝑓: 0.62 (283599 hom.)
• Consequence: C6 NM_000065.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.67
• Publications: 50 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.500128E-5).
• BP6: Variant 5-41199857-G-T is Benign according to our data. Variant chr5-41199857-G-T is described in ClinVar as Benign. ClinVar VariationId is 402458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 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.356C>A	p.Ala119Glu	missense	Exon 4 of 18	NP_000056.2	P13671
	C6	NM_001115131.4		c.356C>A	p.Ala119Glu	missense	Exon 4 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.356C>A	p.Ala119Glu	missense	Exon 4 of 18	ENSP00000338861.5	P13671
	C6	ENST00000263413.7	TSL:1	c.356C>A	p.Ala119Glu	missense	Exon 4 of 18	ENSP00000263413.3	P13671
	C6	ENST00000905250.1		c.356C>A	p.Ala119Glu	missense	Exon 4 of 19	ENSP00000575309.1

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91375 AN: 151846 Hom.: 27559 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.621

GnomAD2 exomes AF: 0.593 AC: 148820 AN: 250990 AF XY: 0.597

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.621 AC: 907173 AN: 1460400 Hom.: 283599 Cov.: 39 AF XY: 0.621 AC XY: 451431 AN XY: 726622

African (AFR) AF: 0.556 AC: 18594 AN: 33442

American (AMR) AF: 0.545 AC: 24358 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 15390 AN: 26114

East Asian (EAS) AF: 0.437 AC: 17336 AN: 39662

South Asian (SAS) AF: 0.602 AC: 51926 AN: 86234

European-Finnish (FIN) AF: 0.597 AC: 31882 AN: 53404

Middle Eastern (MID) AF: 0.602 AC: 3463 AN: 5756

European-Non Finnish (NFE) AF: 0.637 AC: 707585 AN: 1110744

Other (OTH) AF: 0.607 AC: 36639 AN: 60344

GnomAD4 genome AF: 0.602 AC: 91432 AN: 151964 Hom.: 27570 Cov.: 32 AF XY: 0.600 AC XY: 44515 AN XY: 74234

African (AFR) AF: 0.562 AC: 23288 AN: 41424

American (AMR) AF: 0.588 AC: 8975 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2047 AN: 3466

East Asian (EAS) AF: 0.437 AC: 2257 AN: 5160

South Asian (SAS) AF: 0.621 AC: 2997 AN: 4826

European-Finnish (FIN) AF: 0.589 AC: 6210 AN: 10550

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43672 AN: 67964

Other (OTH) AF: 0.621 AC: 1311 AN: 2110

Alfa AF: 0.620 Hom.: 128952

Bravo AF: 0.594

TwinsUK AF: 0.639 AC: 2369

ALSPAC AF: 0.638 AC: 2460

ESP6500AA AF: 0.565 AC: 2488

ESP6500EA AF: 0.631 AC: 5425

ExAC AF: 0.593 AC: 72022

Asia WGS AF: 0.543 AC: 1885 AN: 3478

EpiCase AF: 0.652

EpiControl AF: 0.648

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.30
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.071
MPC		0.038
ClinPred		0.0066	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.50
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: rs1801033; hg19: chr5-41199959; COSMIC: COSV54714885; COSMIC: COSV54714885;