chr12-7108459-C-A

Position:

• chr12-7108459-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016546.4(C1RL):​c.92G>T​(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,448,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: C1RL NM_016546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.116

Genes affected

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]

C1RL-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1RL	NM_016546.4	c.92G>T	p.Gly31Val	missense_variant	2/6	ENST00000266542.9	NP_057630.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1RL	ENST00000266542.9	c.92G>T	p.Gly31Val	missense_variant	2/6	1	NM_016546.4	ENSP00000266542.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1448088 Hom.: 0 Cov.: 31 AF XY: 0.00000696 AC XY: 5 AN XY: 718736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000997

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.92G>T (p.G31V) alteration is located in exon 2 (coding exon 2) of the C1RL gene. This alteration results from a G to T substitution at nucleotide position 92, causing the glycine (G) at amino acid position 31 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.99	D;D;.;D
Vest4		0.41
MutPred		0.47		Gain of catalytic residue at L28 (P = 2e-04);Gain of catalytic residue at L28 (P = 2e-04);Gain of catalytic residue at L28 (P = 2e-04);Gain of catalytic residue at L28 (P = 2e-04);
MVP		0.94
MPC		0.24
ClinPred		0.88	D
GERP RS		3.3
Varity_R		0.28
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -3
DS_AL_spliceai		0.21		Position offset: 20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1418891858; hg19: chr12-7261055;