rs2271708

Variant names:

• chr5-40936439-T-C
• rs2271708
• NM_000587.4:c.382T>C
• C7 p.Cys128Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000587.4(C7):​c.382T>C​(p.Cys128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,254 control chromosomes in the GnomAD database, including 468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 32)
  • Exomes 𝑓: 0.011 (420 hom.)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.55
• Publications: 15 publications found

Genes affected

C7 (HGNC:1346): (complement C7) This gene encodes a serum glycoprotein that forms a membrane attack complex together with complement components C5b, C6, C8, and C9 as part of the terminal complement pathway of the innate immune system. The protein encoded by this gene contains a cholesterol-dependent cytolysin/membrane attack complex/perforin-like (CDC/MACPF) domain and belongs to a large family of structurally related molecules that form pores involved in host immunity and bacterial pathogenesis. This protein initiates membrane attack complex formation by binding the C5b-C6 subcomplex and inserts into the phospholipid bilayer, serving as a membrane anchor. Mutations in this gene are associated with a rare disorder called C7 deficiency. [provided by RefSeq, Nov 2016]

C7 Gene-Disease associations (from GenCC):

• complement component 7 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043652058).
• BP6: Variant 5-40936439-T-C is Benign according to our data. Variant chr5-40936439-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000587.4. 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
	C7	NM_000587.4	MANE Select	c.382T>C	p.Cys128Arg	missense	Exon 5 of 18	NP_000578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C7	ENST00000313164.10	TSL:1 MANE Select	c.382T>C	p.Cys128Arg	missense	Exon 5 of 18	ENSP00000322061.9	P10643
	C7	ENST00000908410.1		c.382T>C	p.Cys128Arg	missense	Exon 5 of 19	ENSP00000578469.1
	C7	ENST00000908412.1		c.382T>C	p.Cys128Arg	missense	Exon 5 of 19	ENSP00000578471.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 152180 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.0398

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0255 AC: 6333 AN: 248440 AF XY: 0.0220

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0113 AC: 16540 AN: 1460956 Hom.: 420 Cov.: 31 AF XY: 0.0113 AC XY: 8240 AN XY: 726764

African (AFR) AF: 0.00179 AC: 60 AN: 33464

American (AMR) AF: 0.101 AC: 4484 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00770 AC: 201 AN: 26104

East Asian (EAS) AF: 0.0435 AC: 1727 AN: 39688

South Asian (SAS) AF: 0.0246 AC: 2116 AN: 86178

European-Finnish (FIN) AF: 0.0144 AC: 768 AN: 53374

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5762

European-Non Finnish (NFE) AF: 0.00581 AC: 6460 AN: 1111438

Other (OTH) AF: 0.0112 AC: 675 AN: 60350

GnomAD4 genome AF: 0.0125 AC: 1900 AN: 152298 Hom.: 48 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74470

African (AFR) AF: 0.00176 AC: 73 AN: 41568

American (AMR) AF: 0.0575 AC: 878 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.0395 AC: 205 AN: 5190

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4832

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00639 AC: 435 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00925 Hom.: 109

Bravo AF: 0.0154

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.00524

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.94
gMVP		0.97
Mutation Taster		=66/34	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2271708;

hg19: chr5-40936541;

COSMIC: COSV57471889;