rs9565308

Variant names:

• chr13-76992279-C-T
• rs9565308
• NM_006493.4:c.173+8C>T

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.173+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,437,784 control chromosomes in the GnomAD database, including 1,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (221 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1613 hom.)
• Consequence: CLN5 NM_006493.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004547
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.562
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, Ambry Genetics, Genomics England PanelApp

ENSG00000283208 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 13-76992279-C-T is Benign according to our data. Variant chr13-76992279-C-T is described in ClinVar as Benign. ClinVar VariationId is 128781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 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.173+8C>T		splice_region intron	N/A	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.173+8C>T		splice_region intron	N/A	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.173+8C>T		splice_region intron	N/A	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.173+8C>T		splice_region intron	N/A	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.173+8C>T		splice_region intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5805 AN: 149034 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0562

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0688 AC: 10355 AN: 150580 AF XY: 0.0632

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0435 AC: 56000 AN: 1288626 Hom.: 1613 Cov.: 35 AF XY: 0.0434 AC XY: 27661 AN XY: 636954

African (AFR) AF: 0.0101 AC: 285 AN: 28166

American (AMR) AF: 0.168 AC: 5750 AN: 34184

Ashkenazi Jewish (ASJ) AF: 0.0339 AC: 696 AN: 20542

East Asian (EAS) AF: 0.159 AC: 4724 AN: 29634

South Asian (SAS) AF: 0.0533 AC: 4256 AN: 79916

European-Finnish (FIN) AF: 0.0536 AC: 1325 AN: 24726

Middle Eastern (MID) AF: 0.0488 AC: 171 AN: 3506

European-Non Finnish (NFE) AF: 0.0358 AC: 36443 AN: 1017130

Other (OTH) AF: 0.0462 AC: 2350 AN: 50822

GnomAD4 genome AF: 0.0390 AC: 5812 AN: 149158 Hom.: 221 Cov.: 32 AF XY: 0.0413 AC XY: 3009 AN XY: 72834

African (AFR) AF: 0.0116 AC: 472 AN: 40752

American (AMR) AF: 0.0993 AC: 1494 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 111 AN: 3446

East Asian (EAS) AF: 0.145 AC: 698 AN: 4818

South Asian (SAS) AF: 0.0561 AC: 250 AN: 4454

European-Finnish (FIN) AF: 0.0406 AC: 406 AN: 9998

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0334 AC: 2252 AN: 67384

Other (OTH) AF: 0.0346 AC: 72 AN: 2080

Alfa AF: 0.0327 Hom.: 28

Bravo AF: 0.0427

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.8
DANN	Benign	0.95
PhyloP100		-0.56
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0020
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: rs9565308; hg19: chr13-77566414;