rs2271709

Variant names:

• chr5-40931255-A-G
• rs2271709
• NM_000587.4:c.138+116A>G

Variant summary

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

The NM_000587.4(C7):​c.138+116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 728,586 control chromosomes in the GnomAD database, including 18,466 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 0.26 (5792 hom., cov: 33)
  • Exomes 𝑓: 0.20 (12674 hom.)
• Consequence: C7 NM_000587.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.749
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4	c.138+116A>G		intron_variant	Intron 3 of 17	ENST00000313164.10	NP_000578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10	c.138+116A>G		intron_variant	Intron 3 of 17	1	NM_000587.4	ENSP00000322061.9

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38931 AN: 152036 Hom.: 5786 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.202 AC: 116657 AN: 576432 Hom.: 12674 AF XY: 0.202 AC XY: 61234 AN XY: 302692

African (AFR) AF: 0.421 AC: 6458 AN: 15346

American (AMR) AF: 0.184 AC: 5166 AN: 28152

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 3556 AN: 19182

East Asian (EAS) AF: 0.254 AC: 7917 AN: 31130

South Asian (SAS) AF: 0.219 AC: 12175 AN: 55560

European-Finnish (FIN) AF: 0.190 AC: 7764 AN: 40764

Middle Eastern (MID) AF: 0.234 AC: 760 AN: 3244

European-Non Finnish (NFE) AF: 0.188 AC: 66329 AN: 352512

Other (OTH) AF: 0.214 AC: 6532 AN: 30542

GnomAD4 genome AF: 0.256 AC: 38961 AN: 152154 Hom.: 5792 Cov.: 33 AF XY: 0.253 AC XY: 18804 AN XY: 74408

African (AFR) AF: 0.422 AC: 17477 AN: 41460

American (AMR) AF: 0.205 AC: 3138 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3468

East Asian (EAS) AF: 0.196 AC: 1018 AN: 5188

South Asian (SAS) AF: 0.213 AC: 1027 AN: 4822

European-Finnish (FIN) AF: 0.184 AC: 1947 AN: 10584

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12945 AN: 68020

Other (OTH) AF: 0.253 AC: 535 AN: 2116

Alfa AF: 0.201 Hom.: 2046

Bravo AF: 0.266

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.46
PhyloP100		-0.75
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: rs2271709; hg19: chr5-40931357;