NM_000065.5:c.356C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.67

Publications

50 publications found

Variant links:

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

C6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C6	NM_000065.5 link	c.356C>A	p.Ala119Glu	missense_variant	Exon 4 of 18	ENST00000337836.10	NP_000056.2	P13671

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C6	ENST00000337836.10 link	c.356C>A	p.Ala119Glu	missense_variant	Exon 4 of 18	1	NM_000065.5	ENSP00000338861.5		P13671

Frequencies

GnomAD3 genomes

AF:

0.602

AC:

91375

AN:

151846

Hom.:

27559

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.621

AC XY:

451431

AN XY:

726622

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17767

35534

53302

71069

88836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18614

37228

55842

74456

93070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.602

AC:

91432

AN:

151964

Hom.:

27570

Cov.:

AF XY:

0.600

AC XY:

44515

AN XY:

74234

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1859

3717

5576

7434

9293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.038

T;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.18

.;T;T

MetaRNN

Benign

0.000045

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

N;N;.

PhyloP100

2.7

PrimateAI

Benign

0.39

PROVEAN

Benign

0.33

N;N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.071

MPC

0.038

ClinPred

0.0066

GERP RS

6.0

Varity_R

0.13

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over