rs200185988

Variant names:

• chr12-7090203-C-A
• rs200185988
• NM_001733.7:c.277G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001733.7(C1R):​c.277G>T​(p.Gly93Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 747,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.73
• Publications: 3 publications found

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15671736).
• BS2: High AC in GnomAd4 at 44 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. 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
	C1R	NM_001733.7	MANE Select	c.277G>T	p.Gly93Cys	missense	Exon 3 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.319G>T	p.Gly107Cys	missense	Exon 3 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.277G>T	p.Gly93Cys	missense	Exon 3 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000903851.1		c.430G>T	p.Gly144Cys	missense	Exon 4 of 12	ENSP00000573910.1
	C1R	ENST00000903850.1		c.349G>T	p.Gly117Cys	missense	Exon 4 of 12	ENSP00000573909.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000275 AC: 54 AN: 196396 AF XY: 0.000323

Gnomad AFR exome AF: 0.000174

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000562

Gnomad OTH exome AF: 0.000578

GnomAD4 exome AF: 0.000311 AC: 185 AN: 595408 Hom.: 0 Cov.: 0 AF XY: 0.000307 AC XY: 99 AN XY: 322778

African (AFR) AF: 0.000235 AC: 4 AN: 17030

American (AMR) AF: 0.0000260 AC: 1 AN: 38498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20440

East Asian (EAS) AF: 0.00 AC: 0 AN: 34626

South Asian (SAS) AF: 0.00 AC: 0 AN: 65472

European-Finnish (FIN) AF: 0.0000783 AC: 4 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.000515 AC: 171 AN: 332246

Other (OTH) AF: 0.000157 AC: 5 AN: 31884

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74322

African (AFR) AF: 0.0000724 AC: 3 AN: 41426

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000494 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000166 AC: 20

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Ehlers-Danlos syndrome, periodontal type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.84	T
PhyloP100		2.7
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.29
ClinPred		0.13	T
GERP RS		5.3
gMVP		0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200185988; hg19: chr12-7242799;