NM_016546.4:c.217G>C

Variant names:

• chr12-7108334-C-G
• rs201343174
• NM_016546.4:c.217G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016546.4(C1RL):​c.217G>C​(p.Ala73Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000299 in 1,614,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: C1RL NM_016546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.116200864).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016546.4. 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
	C1RL	NM_016546.4	MANE Select	c.217G>C	p.Ala73Pro	missense	Exon 2 of 6	NP_057630.2	Q9NZP8
	C1RL	NM_001297640.2		c.217G>C	p.Ala73Pro	missense	Exon 2 of 5	NP_001284569.1
	C1RL	NM_001297642.2		c.217G>C	p.Ala73Pro	missense	Exon 2 of 6	NP_001284571.1	F5GWF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1RL	ENST00000266542.9	TSL:1 MANE Select	c.217G>C	p.Ala73Pro	missense	Exon 2 of 6	ENSP00000266542.4	Q9NZP8
	C1RL	ENST00000544702.5	TSL:1	c.217G>C	p.Ala73Pro	missense	Exon 2 of 6	ENSP00000441885.1	F5GWF3
	C1RL	ENST00000545337.1	TSL:1	c.217G>C	p.Ala73Pro	missense	Exon 2 of 3	ENSP00000442611.1	F5H7C8

Frequencies

GnomAD3 genomes AF: 0.000479 AC: 73 AN: 152264 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000322 AC: 81 AN: 251384 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000280 AC: 409 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000303 AC XY: 220 AN XY: 727236

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5764

European-Non Finnish (NFE) AF: 0.000247 AC: 275 AN: 1112002

Other (OTH) AF: 0.000828 AC: 50 AN: 60392

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152382 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74516

African (AFR) AF: 0.000192 AC: 8 AN: 41596

American (AMR) AF: 0.00124 AC: 19 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68038

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000536

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.42
MPC		0.81
ClinPred		0.32	T
GERP RS		4.3
Varity_R		0.65
gMVP		0.73
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs201343174; hg19: chr12-7260930;