NM_001393344.1:c.221T>G

Variant names:

• chr18-619327-T-G
• rs1216275214
• NM_001393344.1:c.221T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001393344.1(CLUL1):​c.221T>G​(p.Met74Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CLUL1 NM_001393344.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLUL1	NM_001393344.1	c.221T>G	p.Met74Arg	missense_variant	Exon 4 of 10	ENST00000692774.1	NP_001380273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLUL1	ENST00000692774.1	c.221T>G	p.Met74Arg	missense_variant	Exon 4 of 10		NM_001393344.1	ENSP00000510271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135022

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461320 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221T>G (p.M74R) alteration is located in exon 3 (coding exon 2) of the CLUL1 gene. This alteration results from a T to G substitution at nucleotide position 221, causing the methionine (M) at amino acid position 74 to be replaced by an arginine (R). 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	0.34
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;.;T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;.;T;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;.;.;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D
Vest4		0.84
MVP		0.17
MPC		0.98
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.92
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

LitVar

Other links and lift over

dbSNP: rs1216275214; hg19: chr18-619327;