rs114609505

chr5-41195837-G-Achr5-41195837-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000065.5(C6):c.542C>T(p.Thr181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,613,826 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (51 hom.)
• Consequence: C6 NM_000065.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.494

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009862632).
• BP6: Variant 5-41195837-G-A is Benign according to our data. Variant chr5-41195837-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C6	NM_000065.5	c.542C>T	p.Thr181Ile	missense_variant	5/18	ENST00000337836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C6	ENST00000337836.10	c.542C>T	p.Thr181Ile	missense_variant	5/18	1	NM_000065.5	P1

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 774 AN: 152144 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00599 AC: 1504 AN: 251278 Hom.: 8 AF XY: 0.00560 AC XY: 760 AN XY: 135798

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.00930

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00706 AC: 10321 AN: 1461564 Hom.: 51 Cov.: 32 AF XY: 0.00673 AC XY: 4894 AN XY: 727106

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00810

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.00508 AC: 774 AN: 152262 Hom.: 6 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74440

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.00765

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00691 Hom.: 12

Bravo AF: 0.00396

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00673 AC: 817

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	C6: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 02, 2016	- -

C6-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Complement component 6 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.3
Dann	Benign	0.95
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.079	N
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.067
Sift	Benign	0.17	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0020	B;B
Vest4		0.25
MVP		0.53
MPC		0.038
ClinPred		0.0043	T
GERP RS		2.6
Varity_R		0.054
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114609505; hg19: chr5-41195939; COSMIC: COSV54707251; COSMIC: COSV54707251;