NM_001832.4:c.193G>T

Variant names:

• chr6-35795745-C-A
• rs369964160
• NM_001832.4:c.193G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001832.4(CLPS):​c.193G>T​(p.Glu65*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 39)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLPS NM_001832.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

Genes affected

CLPS (HGNC:2085): (colipase) The protein encoded by this gene is a cofactor needed by pancreatic lipase for efficient dietary lipid hydrolysis. It binds to the C-terminal, non-catalytic domain of lipase, thereby stabilizing an active conformation and considerably increasing the overall hydrophobic binding site. The gene product allows lipase to anchor noncovalently to the surface of lipid micelles, counteracting the destabilizing influence of intestinal bile salts. This cofactor is only expressed in pancreatic acinar cells, suggesting regulation of expression by tissue-specific elements. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001832.4. 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
	CLPS	NM_001832.4	MANE Select	c.193G>T	p.Glu65*	stop_gained	Exon 2 of 3	NP_001823.1	P04118
	CLPS	NM_001252597.2		c.151G>T	p.Glu51*	stop_gained	Exon 3 of 4	NP_001239526.1	A0A087WZW1
	CLPS	NM_001252598.2		c.85-468G>T		intron	N/A	NP_001239527.1	A0A087X0Q7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPS	ENST00000259938.7	TSL:1 MANE Select	c.193G>T	p.Glu65*	stop_gained	Exon 2 of 3	ENSP00000259938.2	P04118
	CLPS	ENST00000616014.3	TSL:1	c.85-468G>T		intron	N/A	ENSP00000483589.1	A0A087X0Q7
	CLPS	ENST00000912425.1		c.193G>T	p.Glu65*	stop_gained	Exon 3 of 4	ENSP00000582484.1

Frequencies

GnomAD3 genomes Cov.: 39

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250076 AF XY: 0.00000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460232 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726446

⚠️ 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: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51836

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000565104), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 39

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		1.9
Vest4		0.69
GERP RS		3.2
Mutation Taster		=84/116	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs369964160; hg19: chr6-35763522;