18-627136-C-G

Position:

• chr18-627136-C-G

Variant summary

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

The NM_001393344.1(CLUL1):​c.463C>G​(p.Pro155Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLUL1 NM_001393344.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.240

Genes affected

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

LOC105371952 (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
CLUL1	NM_001393344.1	c.463C>G	p.Pro155Ala	missense_variant	6/10	ENST00000692774.1	NP_001380273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLUL1	ENST00000692774.1	c.463C>G	p.Pro155Ala	missense_variant	6/10		NM_001393344.1	ENSP00000510271.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249426 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461050 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

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

Aug 26, 2024

The c.463C>G (p.P155A) alteration is located in exon 5 (coding exon 4) of the CLUL1 gene. This alteration results from a C to G substitution at nucleotide position 463, causing the proline (P) at amino acid position 155 to be replaced by an alanine (A). 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	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T;T;.;T;T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	.;.;T;T;.;T
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.0	D;D;.;.;D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.024	D;T;.;.;D;.
Sift4G	Benign	0.14	T;D;T;D;T;T
Polyphen		0.98	D;D;.;D;D;D
Vest4		0.45
MutPred		0.51		.;Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);.;.;
MVP		0.71
MPC		0.45
ClinPred		0.75	D
GERP RS		4.0
Varity_R		0.067
gMVP		0.25

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: rs1018647877; hg19: chr18-627136;