18-619260-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001393344.1(CLUL1):c.154G>C(p.Ala52Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLUL1 NM_001393344.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

Genes affected

CLUL1 (HGNC:2096): (clusterin like 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLUL1	NM_001393344.1	c.154G>C	p.Ala52Pro	missense_variant	4/10	ENST00000692774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLUL1	ENST00000692774.1	c.154G>C	p.Ala52Pro	missense_variant	4/10		NM_001393344.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 06, 2022

The c.154G>C (p.A52P) alteration is located in exon 3 (coding exon 2) of the CLUL1 gene. This alteration results from a G to C substitution at nucleotide position 154, causing the alanine (A) at amino acid position 52 to be replaced by a proline (P). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;.;D;D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.47	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.89, 0.86	.;P;P;.;P;P;P
Vest4		0.85, 0.79, 0.82, 0.79, 0.84
MutPred		0.86		.;.;Loss of MoRF binding (P = 0.0587);.;Loss of MoRF binding (P = 0.0587);.;.;
MVP		0.34
MPC		0.95
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-619260;