rs17608

Variant names:

• chr19-39735006-G-A
• rs17608
• NM_001828.6:c.83C>T

Variant summary

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

The NM_001828.6(CLC):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 1,609,258 control chromosomes in the GnomAD database, including 355,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (34939 hom., cov: 31)
  • Exomes 𝑓: 0.66 (320311 hom.)
• Consequence: CLC NM_001828.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592

Genes affected

CLC (HGNC:2014): (Charcot-Leyden crystal galectin) Lysophospholipases are enzymes that act on biological membranes to regulate the multifunctional lysophospholipids. The protein encoded by this gene is a lysophospholipase expressed in eosinophils and basophils. It hydrolyzes lysophosphatidylcholine to glycerophosphocholine and a free fatty acid. This protein may possess carbohydrate or IgE-binding activities. It is both structurally and functionally related to the galectin family of beta-galactoside binding proteins. It may be associated with inflammation and some myeloid leukemias. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.081519E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLC	NM_001828.6	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 4	ENST00000221804.5	NP_001819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLC	ENST00000221804.5	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 4	1	NM_001828.6	ENSP00000221804.3

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101832 AN: 151888 Hom.: 34896 Cov.: 31

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.624

GnomAD3 exomes AF: 0.616 AC: 154504 AN: 251020 Hom.: 50248 AF XY: 0.625 AC XY: 84795 AN XY: 135648

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.317

Gnomad SAS exome AF: 0.687

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.658 AC: 958718 AN: 1457252 Hom.: 320311 Cov.: 33 AF XY: 0.659 AC XY: 478274 AN XY: 725208

Gnomad4 AFR exome AF: 0.778

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.694

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.685

Gnomad4 FIN exome AF: 0.691

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.670 AC: 101916 AN: 152006 Hom.: 34939 Cov.: 31 AF XY: 0.665 AC XY: 49423 AN XY: 74294

Gnomad4 AFR AF: 0.772

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.697

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.671

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.671

Gnomad4 OTH AF: 0.618

Alfa AF: 0.657 Hom.: 70595

Bravo AF: 0.654

TwinsUK AF: 0.680 AC: 2523

ALSPAC AF: 0.681 AC: 2623

ESP6500AA AF: 0.771 AC: 3398

ESP6500EA AF: 0.667 AC: 5735

ExAC AF: 0.631 AC: 76585

Asia WGS AF: 0.510 AC: 1774 AN: 3478

EpiCase AF: 0.660

EpiControl AF: 0.655

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.15
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.000090	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.95	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.010
Sift	Benign	0.60	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.11
ClinPred		0.00028	T
GERP RS		0.72
Varity_R		0.079
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17608; hg19: chr19-40225646; COSMIC: COSV55684965;