chr18-618032-G-A

Variant names:

• chr18-618032-G-A
• rs766168896
• NM_001393344.1:c.32G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001393344.1(CLUL1):​c.32G>A​(p.Cys11Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C11F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLUL1 NM_001393344.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.503
• Publications: 0 publications found

Genes affected

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022131473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393344.1. 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
	CLUL1	NM_001393344.1	MANE Select	c.32G>A	p.Cys11Tyr	missense	Exon 3 of 10	NP_001380273.1	Q15846
	CLUL1	NM_001289036.3		c.32G>A	p.Cys11Tyr	missense	Exon 4 of 11	NP_001275965.2	Q15846
	CLUL1	NM_001318522.2		c.32G>A	p.Cys11Tyr	missense	Exon 2 of 9	NP_001305451.1	Q15846

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLUL1	ENST00000692774.1	MANE Select	c.32G>A	p.Cys11Tyr	missense	Exon 3 of 10	ENSP00000510271.1	Q15846
	CLUL1	ENST00000338387.11	TSL:1	c.32G>A	p.Cys11Tyr	missense	Exon 2 of 9	ENSP00000341128.6	Q15846
	CLUL1	ENST00000400606.6	TSL:1	c.32G>A	p.Cys11Tyr	missense	Exon 2 of 9	ENSP00000383449.2	Q15846

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.2
DANN	Benign	0.67
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.50
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.55		Loss of sheet (P = 0.0025)
MVP		0.040
MPC		0.38
ClinPred		0.053	T
GERP RS		0.42
Varity_R		0.042
gMVP		0.067
Mutation Taster		=98/2	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: rs766168896; hg19: chr18-618032;