NM_000587.4:c.2166-223A>T

Variant names:

• chr5-40979502-A-T
• rs2329434
• NM_000587.4:c.2166-223A>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.2166-223A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,094 control chromosomes in the GnomAD database, including 2,961 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 (2961 hom., cov: 31)
• Consequence: C7 NM_000587.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.457
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4	c.2166-223A>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.2166-223A>T		intron_variant	Intron 16 of 17	1	NM_000587.4	ENSP00000322061.9

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27369 AN: 151976 Hom.: 2960 Cov.: 31

Gnomad AFR AF: 0.0662

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27378 AN: 152094 Hom.: 2961 Cov.: 31 AF XY: 0.187 AC XY: 13873 AN XY: 74322

African (AFR) AF: 0.0663 AC: 2754 AN: 41548

American (AMR) AF: 0.162 AC: 2482 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 977 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1515 AN: 5152

South Asian (SAS) AF: 0.323 AC: 1554 AN: 4812

European-Finnish (FIN) AF: 0.244 AC: 2572 AN: 10546

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

European-Non Finnish (NFE) AF: 0.218 AC: 14797 AN: 67976

Other (OTH) AF: 0.208 AC: 439 AN: 2106

Alfa AF: 0.118 Hom.: 226

Bravo AF: 0.166

Asia WGS AF: 0.305 AC: 1056 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.1
DANN	Benign	0.70
PhyloP100		0.46
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: rs2329434; hg19: chr5-40979604;