rs2766597

chr6-35797266-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001832.4(CLPS):c.23T>C(p.Leu8Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0153 in 1,603,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.038 (0 hom., cov: 44)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: CLPS NM_001832.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51

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]

LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003546685).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPS	NM_001832.4	c.23T>C	p.Leu8Pro	missense_variant	1/3	ENST00000259938.7
CLPS	NM_001252598.2	c.23T>C	p.Leu8Pro	missense_variant	1/2
CLPS	NM_001252597.2	c.-118T>C		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPS	ENST00000259938.7	c.23T>C	p.Leu8Pro	missense_variant	1/3	1	NM_001832.4	P1
CLPS	ENST00000616014.3	c.23T>C	p.Leu8Pro	missense_variant	1/2	1
LHFPL5	ENST00000651132.1	c.-346A>G		5_prime_UTR_variant	1/7			P1

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5668 AN: 151126 Hom.: 0 Cov.: 44

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0374

GnomAD3 exomes AF: 0.0134 AC: 3348 AN: 249490 Hom.: 0 AF XY: 0.0112 AC XY: 1514 AN XY: 134986

Gnomad AFR exome AF: 0.0964

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0130 AC: 18839 AN: 1452696 Hom.: 0 Cov.: 32 AF XY: 0.0123 AC XY: 8861 AN XY: 722908

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0376 AC: 5684 AN: 151244 Hom.: 0 Cov.: 44 AF XY: 0.0356 AC XY: 2638 AN XY: 74032

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0366

Alfa AF: 0.0169 Hom.: 35

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.0826 AC: 364

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.0189 AC: 2293

Asia WGS AF: 0.00982 AC: 35 AN: 3478

EpiCase AF: 0.00944

EpiControl AF: 0.0117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.31
MPC		1.4
ClinPred		0.037	T
GERP RS		4.9
Varity_R		0.87
gMVP		0.81

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: rs2766597; hg19: chr6-35765043;