rs2876849

Variant names:

• chr5-40979688-A-T
• rs2876849
• NM_000587.4:c.2166-37A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000587.4(C7):​c.2166-37A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,563,806 control chromosomes in the GnomAD database, including 37,556 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 0.18 (2967 hom., cov: 31)
  • Exomes 𝑓: 0.22 (34589 hom.)
• Consequence: C7 NM_000587.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4	c.2166-37A>T		intron_variant	Intron 16 of 17	ENST00000313164.10	NP_000578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10	c.2166-37A>T		intron_variant	Intron 16 of 17	1	NM_000587.4	ENSP00000322061.9

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27348 AN: 151848 Hom.: 2966 Cov.: 31

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.223 AC: 51723 AN: 232424 AF XY: 0.233

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.215 AC: 303666 AN: 1411840 Hom.: 34589 Cov.: 23 AF XY: 0.220 AC XY: 153397 AN XY: 698484

African (AFR) AF: 0.0631 AC: 2048 AN: 32446

American (AMR) AF: 0.147 AC: 6248 AN: 42432

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 6817 AN: 24782

East Asian (EAS) AF: 0.269 AC: 10412 AN: 38724

South Asian (SAS) AF: 0.305 AC: 24655 AN: 80730

European-Finnish (FIN) AF: 0.239 AC: 12524 AN: 52360

Middle Eastern (MID) AF: 0.304 AC: 1423 AN: 4688

European-Non Finnish (NFE) AF: 0.210 AC: 226252 AN: 1077466

Other (OTH) AF: 0.228 AC: 13287 AN: 58212

GnomAD4 genome AF: 0.180 AC: 27357 AN: 151966 Hom.: 2967 Cov.: 31 AF XY: 0.187 AC XY: 13868 AN XY: 74282

African (AFR) AF: 0.0661 AC: 2741 AN: 41462

American (AMR) AF: 0.162 AC: 2478 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 975 AN: 3468

East Asian (EAS) AF: 0.295 AC: 1524 AN: 5164

South Asian (SAS) AF: 0.322 AC: 1543 AN: 4798

European-Finnish (FIN) AF: 0.244 AC: 2578 AN: 10550

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14796 AN: 67950

Other (OTH) AF: 0.208 AC: 438 AN: 2104

Alfa AF: 0.213 Hom.: 729

Bravo AF: 0.166

Asia WGS AF: 0.305 AC: 1057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.76
PhyloP100		2.3
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs2876849; hg19: chr5-40979790;