12-7108472-G-C

Position:

• chr12-7108472-G-C

Variant summary

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

The NM_016546.4(C1RL):​c.79C>G​(p.Leu27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1RL NM_016546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.221

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:27461): (C1RL antisense RNA 1)

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.79C>G	p.Leu27Val	missense_variant	2/6	ENST00000266542.9	NP_057630.2
C1RL-AS1	NR_026947.1	n.165G>C		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1RL	ENST00000266542.9	c.79C>G	p.Leu27Val	missense_variant	2/6	1	NM_016546.4	ENSP00000266542	P1
C1RL-AS1	ENST00000535078.2	n.150G>C		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 26, 2022

The c.79C>G (p.L27V) alteration is located in exon 2 (coding exon 2) of the C1RL gene. This alteration results from a C to G substitution at nucleotide position 79, causing the leucine (L) at amino acid position 27 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	0.11
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	0.99	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.18	T;D;T;T
Sift4G	Uncertain	0.021	D;D;.;D
Polyphen		0.80	P;D;.;P
Vest4		0.32
MutPred		0.45		Gain of catalytic residue at L28 (P = 0);Gain of catalytic residue at L28 (P = 0);Gain of catalytic residue at L28 (P = 0);Gain of catalytic residue at L28 (P = 0);
MVP		0.94
MPC		0.46
ClinPred		0.86	D
GERP RS		0.093
Varity_R		0.075
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs775183495; hg19: chr12-7261068;