rs1800209

Variant names:

• chr13-77000848-A-G
• rs1800209
• NM_006493.4:c.956A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-77000848-A-G
• chr13-77000848-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006493.4(CLN5):​c.956A>G​(p.Lys319Arg) variant causes a missense change. The variant allele was found at a frequency of 0.104 in 1,603,422 control chromosomes in the GnomAD database, including 14,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K319E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (4375 hom., cov: 32)
  • Exomes 𝑓: 0.095 (10044 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 3.82
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035348833).
• BP6: Variant 13-77000848-A-G is Benign according to our data. Variant chr13-77000848-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	NM_006493.4	MANE Select	c.956A>G	p.Lys319Arg	missense	Exon 4 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.*405A>G		3_prime_UTR	Exon 5 of 5	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.956A>G	p.Lys319Arg	missense	Exon 4 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.956A>G	p.Lys319Arg	missense	Exon 4 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.565+4721A>G		intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28876 AN: 152026 Hom.: 4360 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.141 AC: 34273 AN: 242548 AF XY: 0.128

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.0982

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.0926

Gnomad NFE exome AF: 0.0790

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.0947 AC: 137381 AN: 1451278 Hom.: 10044 Cov.: 33 AF XY: 0.0927 AC XY: 66897 AN XY: 721282

African (AFR) AF: 0.428 AC: 14036 AN: 32768

American (AMR) AF: 0.237 AC: 10135 AN: 42676

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 2438 AN: 25680

East Asian (EAS) AF: 0.271 AC: 10740 AN: 39604

South Asian (SAS) AF: 0.0893 AC: 7482 AN: 83830

European-Finnish (FIN) AF: 0.0965 AC: 5128 AN: 53138

Middle Eastern (MID) AF: 0.144 AC: 820 AN: 5710

European-Non Finnish (NFE) AF: 0.0719 AC: 79643 AN: 1107978

Other (OTH) AF: 0.116 AC: 6959 AN: 59894

GnomAD4 genome AF: 0.190 AC: 28943 AN: 152144 Hom.: 4375 Cov.: 32 AF XY: 0.191 AC XY: 14213 AN XY: 74412

African (AFR) AF: 0.417 AC: 17280 AN: 41448

American (AMR) AF: 0.191 AC: 2916 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3472

East Asian (EAS) AF: 0.270 AC: 1399 AN: 5176

South Asian (SAS) AF: 0.0926 AC: 447 AN: 4828

European-Finnish (FIN) AF: 0.0920 AC: 975 AN: 10602

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0743 AC: 5051 AN: 68006

Other (OTH) AF: 0.164 AC: 346 AN: 2114

Alfa AF: 0.113 Hom.: 5066

Bravo AF: 0.210

TwinsUK AF: 0.0744 AC: 276

ALSPAC AF: 0.0688 AC: 265

ESP6500AA AF: 0.402 AC: 1771

ESP6500EA AF: 0.0787 AC: 676

ExAC AF: 0.141 AC: 17061

Asia WGS AF: 0.202 AC: 702 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	Neuronal ceroid lipofuscinosis 5 (3)
-	-	3	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.0	N
PhyloP100		3.8
PrimateAI	Benign	0.30	T
REVEL	Benign	0.29
Polyphen		0.0	B
MPC		0.14
ClinPred		0.0011	T
GERP RS		5.0
Varity_R		0.057
Mutation Taster		=97/3	polymorphism (auto)

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: rs1800209; hg19: chr13-77574983; COSMIC: COSV62918786; COSMIC: COSV62918786;