rs138611001

Variant names:

• chr13-77000471-C-A
• rs138611001
• NM_006493.4:c.579C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006493.4(CLN5):​c.579C>A​(p.Asn193Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,611,868 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 32)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: 0.522
• Publications: 15 publications found

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

ENSG00000283208 (HGNC:):

FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

FBXL3 Gene-Disease associations (from GenCC):

• intellectual disability, short stature, facial anomalies, and joint dislocations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009227604).
• BP6: Variant 13-77000471-C-A is Benign according to our data. Variant chr13-77000471-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136794.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00897 (1357/151204) while in subpopulation NFE AF = 0.0153 (1037/67890). AF 95% confidence interval is 0.0145. There are 8 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006493.4. 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
	CLN5	NM_006493.4	MANE Select	c.579C>A	p.Asn193Lys	missense	Exon 4 of 4	NP_006484.2
	CLN5	NM_001366624.2		c.*28C>A		3_prime_UTR	Exon 5 of 5	NP_001353553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.579C>A	p.Asn193Lys	missense	Exon 4 of 4	ENSP00000366673.5
	CLN5	ENST00000636183.2	TSL:1	c.579C>A	p.Asn193Lys	missense	Exon 4 of 4	ENSP00000490181.2
	ENSG00000283208	ENST00000638147.2	TSL:5	c.565+4344C>A		intron	N/A	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1357 AN: 151112 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00422

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0107

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00933 AC: 2333 AN: 250114 AF XY: 0.00983

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.00788

GnomAD4 exome AF: 0.0137 AC: 20037 AN: 1460664 Hom.: 160 Cov.: 33 AF XY: 0.0136 AC XY: 9916 AN XY: 726486

African (AFR) AF: 0.00248 AC: 83 AN: 33446

American (AMR) AF: 0.00415 AC: 185 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 164 AN: 26104

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39666

South Asian (SAS) AF: 0.0104 AC: 897 AN: 86002

European-Finnish (FIN) AF: 0.00560 AC: 299 AN: 53356

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17636 AN: 1111358

Other (OTH) AF: 0.0122 AC: 738 AN: 60348

GnomAD4 genome AF: 0.00897 AC: 1357 AN: 151204 Hom.: 8 Cov.: 32 AF XY: 0.00831 AC XY: 613 AN XY: 73772

African (AFR) AF: 0.00262 AC: 108 AN: 41162

American (AMR) AF: 0.00421 AC: 64 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.0107 AC: 51 AN: 4770

European-Finnish (FIN) AF: 0.00605 AC: 62 AN: 10256

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0153 AC: 1037 AN: 67890

Other (OTH) AF: 0.00713 AC: 15 AN: 2104

Alfa AF: 0.0134 Hom.: 58

Bravo AF: 0.00836

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.00965 AC: 1172

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0120

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Neuronal ceroid lipofuscinosis 5 (6)
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.0020
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.52
PrimateAI	Uncertain	0.58	T
REVEL	Uncertain	0.56
Polyphen		1.0	D
MutPred		0.66		Gain of methylation at N193 (P = 0.0039)
MVP		0.97
MPC		0.78
ClinPred		0.029	T
GERP RS		4.1
Varity_R		0.35
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs138611001; hg19: chr13-77574606; COSMIC: COSV99053054; COSMIC: COSV99053054;