rs114609505

Variant names:

• chr5-41195837-G-A
• rs114609505
• NM_000065.5:c.542C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-41195837-G-A
• chr5-41195837-G-T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:6
• Conservation: PhyloP100: 0.494
• Publications: 11 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 -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 Benign/Likely_benign. ClinVar VariationId is 377318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.542C>T	p.Thr181Ile	missense	Exon 5 of 18	NP_000056.2
	C6	NM_001115131.4		c.542C>T	p.Thr181Ile	missense	Exon 5 of 18	NP_001108603.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C6	ENST00000337836.10	TSL:1 MANE Select	c.542C>T	p.Thr181Ile	missense	Exon 5 of 18	ENSP00000338861.5
	C6	ENST00000263413.7	TSL:1	c.542C>T	p.Thr181Ile	missense	Exon 5 of 18	ENSP00000263413.3
	C6	ENST00000905250.1		c.542C>T	p.Thr181Ile	missense	Exon 5 of 19	ENSP00000575309.1

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

GnomAD2 exomes AF: 0.00599 AC: 1504 AN: 251278 AF XY: 0.00560

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.00125 AC: 56 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0164 AC: 876 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00810 AC: 9010 AN: 1111790

Other (OTH) AF: 0.00518 AC: 313 AN: 60384

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

African (AFR) AF: 0.000987 AC: 41 AN: 41552

American (AMR) AF: 0.00164 AC: 25 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00765 AC: 520 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00653 Hom.: 15

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	C6-related disorder (1)
-	-	1	Complement component 6 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.49
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.067
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

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