chr12-7108466-G-T

Position:

• chr12-7108466-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016546.4(C1RL):​c.85C>A​(p.Leu29Ile) 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. 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: 2.37

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37422025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1RL	NM_016546.4	c.85C>A	p.Leu29Ile	missense_variant	2/6	ENST00000266542.9	NP_057630.2
C1RL-AS1	NR_026947.1	n.159G>T		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1RL	ENST00000266542.9	c.85C>A	p.Leu29Ile	missense_variant	2/6	1	NM_016546.4	ENSP00000266542	P1
C1RL-AS1	ENST00000535078.2	n.144G>T		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 07, 2021

The c.85C>A (p.L29I) alteration is located in exon 2 (coding exon 2) of the C1RL gene. This alteration results from a C to A substitution at nucleotide position 85, causing the leucine (L) at amino acid position 29 to be replaced by an isoleucine (I). 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	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T;T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	0.65	D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.093
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.025	D;D;.;D
Polyphen		0.99	D;D;.;D
Vest4		0.39
MutPred		0.42		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		0.70
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1938830311; hg19: chr12-7261062; COSMIC: COSV56925969; COSMIC: COSV56925969;