13-76992000-G-C

Variant names:

• chr13-76992000-G-C
• rs202118652
• ENST00000636183.2:c.-99G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000636183.2(CLN5):​c.-99G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,601,892 control chromosomes in the GnomAD database, including 1 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 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -2.40
• Publications: 2 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ENSG00000283208 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044178665).
• BP6: Variant 13-76992000-G-C is Benign according to our data. Variant chr13-76992000-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205123.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00197 (300/152318) while in subpopulation AFR AF = 0.00645 (268/41576). AF 95% confidence interval is 0.00581. There are 1 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	NM_006493.4	MANE Select	c.-99G>C		upstream_gene	N/A	NP_006484.2
	CLN5	NM_001366624.2		c.-99G>C		upstream_gene	N/A	NP_001353553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000636183.2	TSL:1	c.-99G>C		5_prime_UTR	Exon 1 of 4	ENSP00000490181.2
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-99G>C		upstream_gene	N/A	ENSP00000366673.5
	ENSG00000283208	ENST00000638147.2	TSL:5	c.-99G>C		upstream_gene	N/A	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000551 AC: 118 AN: 214040 AF XY: 0.000462

Gnomad AFR exome AF: 0.00507

Gnomad AMR exome AF: 0.000576

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000866

Gnomad OTH exome AF: 0.000557

GnomAD4 exome AF: 0.000307 AC: 445 AN: 1449574 Hom.: 0 Cov.: 34 AF XY: 0.000298 AC XY: 215 AN XY: 720728

African (AFR) AF: 0.00748 AC: 249 AN: 33278

American (AMR) AF: 0.000547 AC: 24 AN: 43856

Ashkenazi Jewish (ASJ) AF: 0.00275 AC: 71 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 85084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48138

Middle Eastern (MID) AF: 0.00183 AC: 10 AN: 5472

European-Non Finnish (NFE) AF: 0.0000307 AC: 34 AN: 1108694

Other (OTH) AF: 0.000902 AC: 54 AN: 59888

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74478

African (AFR) AF: 0.00645 AC: 268 AN: 41576

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000877 Hom.: 0

Bravo AF: 0.00201

ESP6500AA AF: 0.00285 AC: 11

ESP6500EA AF: 0.000130 AC: 1

ExAC AF: 0.000504 AC: 59

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Neuronal ceroid lipofuscinosis (2)
-	-	2	Neuronal ceroid lipofuscinosis 5 (2)
-	-	2	not specified (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	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.60
DANN	Uncertain	0.98
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
PhyloP100		-2.4
PrimateAI	Uncertain	0.59	T
MutPred		0.35		Loss of loop (P = 0.0112)
ClinPred		0.018	T
GERP RS		-1.9
PromoterAI		0.015	Neutral
Mutation Taster		=99/1	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: rs202118652; hg19: chr13-77566135;