chr12-7091446-C-T

Variant names:

• chr12-7091446-C-T
• rs145563624
• NM_001733.7:c.231+6G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001733.7(C1R):​c.231+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 754,606 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: C1R NM_001733.7 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0570

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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-7091446-C-T is Benign according to our data. Variant chr12-7091446-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2500100.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7091446-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 477 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.231+6G>A		splice_region_variant, intron_variant	Intron 2 of 10	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.273+6G>A		splice_region_variant, intron_variant	Intron 2 of 10		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.231+6G>A		splice_region_variant, intron_variant	Intron 2 of 10		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000896 AC: 188 AN: 209912 AF XY: 0.000736

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000866

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000584 AC: 352 AN: 602310 Hom.: 1 Cov.: 0 AF XY: 0.000490 AC XY: 160 AN XY: 326638

Gnomad4 AFR exome AF: 0.0120 AC: 206 AN: 17160

Gnomad4 AMR exome AF: 0.00120 AC: 47 AN: 39282

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 20504

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 34874

Gnomad4 SAS exome AF: 0.0000455 AC: 3 AN: 65896

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51578

Gnomad4 NFE exome AF: 0.000119 AC: 40 AN: 336696

Gnomad4 Remaining exome AF: 0.00146 AC: 47 AN: 32206

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74474

Gnomad4 AFR AF: 0.0101 AC: 0.0100558 AN: 0.0100558

Gnomad4 AMR AF: 0.00235 AC: 0.00235325 AN: 0.00235325

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.000161712 AN: 0.000161712

Gnomad4 OTH AF: 0.00379 AC: 0.00379147 AN: 0.00379147

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00393

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Benign:1

Jul 25, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 1.0% (416/41446) including 2 homozygotes (https://gnomad.broadinstitute.org/variant/12-7091446-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools do not suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.3
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs145563624; hg19: chr12-7244042;