5-40949895-C-T

Variant names:

• chr5-40949895-C-T
• rs1450656
• NM_000587.4:c.983-9C>T

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.983-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,501,092 control chromosomes in the GnomAD database, including 309,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33663 hom., cov: 31)
  • Exomes 𝑓: 0.64 (275474 hom.)
• Consequence: C7 NM_000587.4 intron
• Scores: Splicing: ADA: 0.00001686
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.512
• Publications: 11 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 (BayesDel_noAF=-0.9).
• BP6: Variant 5-40949895-C-T is Benign according to our data. Variant chr5-40949895-C-T is described in ClinVar as Benign. ClinVar VariationId is 1170113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4	c.983-9C>T		intron_variant	Intron 8 of 17	ENST00000313164.10	NP_000578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10	c.983-9C>T		intron_variant	Intron 8 of 17	1	NM_000587.4	ENSP00000322061.9

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100905 AN: 151838 Hom.: 33640 Cov.: 31

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.653

GnomAD2 exomes AF: 0.644 AC: 121860 AN: 189342 AF XY: 0.642

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.675

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.638 AC: 860346 AN: 1349136 Hom.: 275474 Cov.: 21 AF XY: 0.636 AC XY: 427226 AN XY: 671244

African (AFR) AF: 0.736 AC: 23134 AN: 31436

American (AMR) AF: 0.610 AC: 23202 AN: 38036

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 16581 AN: 24870

East Asian (EAS) AF: 0.655 AC: 24815 AN: 37896

South Asian (SAS) AF: 0.607 AC: 48137 AN: 79264

European-Finnish (FIN) AF: 0.678 AC: 34641 AN: 51114

Middle Eastern (MID) AF: 0.671 AC: 3673 AN: 5470

European-Non Finnish (NFE) AF: 0.634 AC: 649735 AN: 1024630

Other (OTH) AF: 0.646 AC: 36428 AN: 56420

GnomAD4 genome AF: 0.665 AC: 100977 AN: 151956 Hom.: 33663 Cov.: 31 AF XY: 0.665 AC XY: 49398 AN XY: 74246

African (AFR) AF: 0.732 AC: 30360 AN: 41458

American (AMR) AF: 0.627 AC: 9544 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2328 AN: 3466

East Asian (EAS) AF: 0.682 AC: 3517 AN: 5158

South Asian (SAS) AF: 0.606 AC: 2921 AN: 4818

European-Finnish (FIN) AF: 0.689 AC: 7276 AN: 10566

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42951 AN: 67942

Other (OTH) AF: 0.656 AC: 1385 AN: 2110

Alfa AF: 0.641 Hom.: 46448

Bravo AF: 0.661

Asia WGS AF: 0.645 AC: 2244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.48
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs1450656; hg19: chr5-40949997; COSMIC: COSV57475097; COSMIC: COSV57475097;