rs1268502139

Variant names:

• chr13-76991952-A-C
• rs1268502139
• ENST00000636183.2:c.-147A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-76991952-A-C
• chr13-76991952-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The ENST00000636183.2(CLN5):​c.-147A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,561,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.461
• Publications: 4 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]

CLN5 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women's Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ENSG00000283208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• BP6: Variant 13-76991952-A-C is Benign according to our data. Variant chr13-76991952-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554902.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636183.2. 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.-147A>C		upstream_gene	N/A	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.-147A>C		upstream_gene	N/A	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000636183.2	TSL:1	c.-147A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000490181.2	O75503
	CLN5	ENST00000636183.2	TSL:1	c.-147A>C		5_prime_UTR	Exon 1 of 4	ENSP00000490181.2	O75503
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-147A>C		upstream_gene	N/A	ENSP00000366673.5	O75503

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152016 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000629 AC: 1 AN: 158932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 35 AN: 1409884 Hom.: 0 Cov.: 32 AF XY: 0.0000301 AC XY: 21 AN XY: 698140

African (AFR) AF: 0.0000308 AC: 1 AN: 32494

American (AMR) AF: 0.00 AC: 0 AN: 38412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37080

South Asian (SAS) AF: 0.00 AC: 0 AN: 81320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.0000312 AC: 34 AN: 1090650

Other (OTH) AF: 0.00 AC: 0 AN: 58700

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152016 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Neuronal ceroid lipofuscinosis 5 (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.5
DANN	Benign	0.63
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.00093	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.98	T
PhyloP100		-0.46
PromoterAI		-0.098	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1268502139;

hg19: chr13-77566087;