6-35797266-A-G

Variant names:

• chr6-35797266-A-G
• rs2766597
• NM_001832.4:c.23T>C

Variant summary

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

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.

• 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
• Publications: 16 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]

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]

LHFPL5 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 67

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Variant has high frequency in the AFR (0.0972) population. However there is too low homozygotes in high coverage region: (expected more than 93, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.003546685).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPS	NM_001832.4	MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 3	NP_001823.1
	CLPS	NM_001252598.2		c.23T>C	p.Leu8Pro	missense	Exon 1 of 2	NP_001239527.1
	CLPS	NM_001252597.2		c.-118T>C		5_prime_UTR	Exon 1 of 4	NP_001239526.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPS	ENST00000259938.7	TSL:1 MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 3	ENSP00000259938.2
	CLPS	ENST00000616014.3	TSL:1	c.23T>C	p.Leu8Pro	missense	Exon 1 of 2	ENSP00000483589.1
	LHFPL5	ENST00000651132.1		c.-346A>G		5_prime_UTR	Exon 1 of 7	ENSP00000498322.1

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

GnomAD2 exomes AF: 0.0134 AC: 3348 AN: 249490 AF XY: 0.0112

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 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

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

African (AFR) AF: 0.100 AC: 3212 AN: 32086

American (AMR) AF: 0.0124 AC: 550 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86238

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53254

Middle Eastern (MID) AF: 0.0170 AC: 97 AN: 5720

European-Non Finnish (NFE) AF: 0.0125 AC: 13814 AN: 1105180

Other (OTH) AF: 0.0160 AC: 962 AN: 59976

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

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

African (AFR) AF: 0.105 AC: 4273 AN: 40740

American (AMR) AF: 0.0214 AC: 326 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10628

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0143 AC: 973 AN: 67830

Other (OTH) AF: 0.0366 AC: 77 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0192 Hom.: 37

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 v4.9

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
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.31
MPC		1.4
ClinPred		0.037	T
GERP RS		4.9
PromoterAI		-0.041	Neutral
Varity_R		0.87
gMVP		0.81
Mutation Taster		=79/21	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: rs2766597; hg19: chr6-35765043;