Genetic Variant C6:c.-21+143G>C (chr5-41213233-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_000065.5(C6):c.-21+143G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 216,400 control chromosomes in the GnomAD database, including 7,793 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 0.23 ( 4989 hom., cov: 32)

Exomes 𝑓: 0.29 ( 2804 hom. )

Consequence

C6
NM_000065.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.882

Publications

5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

C6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 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.-21+143G>C		intron	N/A	NP_000056.2	P13671
	C6	NM_001115131.4		c.-20-9983G>C		intron	N/A	NP_001108603.2	P13671

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C6	ENST00000337836.10	TSL:1 MANE Select	c.-21+143G>C	intron	N/A	ENSP00000338861.5	P13671
C6	ENST00000263413.7	TSL:1	c.-20-9983G>C	intron	N/A	ENSP00000263413.3	P13671
C6	ENST00000905250.1		c.-21+143G>C	intron	N/A	ENSP00000575309.1

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35147

AN:

151780

Hom.:

4991

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0754

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.378

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.251

GnomAD4 exome

AF:

0.289

AC:

18621

AN:

64500

Hom.:

2804

AF XY:

0.288

AC XY:

9088

AN XY:

31610

show subpopulations

African (AFR)

AF:

0.0540

AC:

AN:

1130

American (AMR)

AF:

0.189

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

AN:

400

East Asian (EAS)

AF:

0.108

AC:

AN:

232

South Asian (SAS)

AF:

0.208

AC:

255

AN:

1228

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.190

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.298

AC:

17605

AN:

59120

Other (OTH)

AF:

0.252

AC:

546

AN:

2164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

670

1340

2010

2680

3350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.231

AC:

35137

AN:

151900

Hom.:

4989

Cov.:

AF XY:

0.233

AC XY:

17307

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.0752

AC:

3117

AN:

41466

American (AMR)

AF:

0.208

AC:

3165

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

750

AN:

3470

East Asian (EAS)

AF:

0.123

AC:

635

AN:

5168

South Asian (SAS)

AF:

0.203

AC:

975

AN:

4812

European-Finnish (FIN)

AF:

0.378

AC:

3976

AN:

10518

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21710

AN:

67902

Other (OTH)

AF:

0.249

AC:

526

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1323

2646

3970

5293

6616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.183

Hom.:

493

Bravo

AF:

0.207

Asia WGS

AF:

0.137

AC:

477

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.9

(source)

DANN

Benign

0.57

PhyloP100

0.88

PromoterAI

-0.010

Neutral

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over