rs654196

Variant names:

• chr13-76991837-A-G
• rs654196
• ENST00000636183.2:c.-262A>G

Variant summary

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

The ENST00000636183.2(CLN5):​c.-262A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,328,844 control chromosomes in the GnomAD database, including 243,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (20541 hom., cov: 32)
  • Exomes 𝑓: 0.60 (222841 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.412
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-76991837-A-G is Benign according to our data. Variant chr13-76991837-A-G is described in ClinVar as Benign. ClinVar VariationId is 670727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4	c.-262A>G		upstream_gene_variant		ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.-262A>G		upstream_gene_variant			NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.-262A>G		upstream_gene_variant		1	NM_006493.4	ENSP00000366673.5
ENSG00000283208	ENST00000638147.2	c.-262A>G		upstream_gene_variant		5		ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.467 AC: 71043 AN: 151988 Hom.: 20542 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.602 AC: 707938 AN: 1176738 Hom.: 222841 Cov.: 17 AF XY: 0.598 AC XY: 352312 AN XY: 589576

African (AFR) AF: 0.125 AC: 3442 AN: 27598

American (AMR) AF: 0.403 AC: 14248 AN: 35314

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 15385 AN: 23800

East Asian (EAS) AF: 0.247 AC: 8595 AN: 34842

South Asian (SAS) AF: 0.402 AC: 29922 AN: 74372

European-Finnish (FIN) AF: 0.634 AC: 21156 AN: 33388

Middle Eastern (MID) AF: 0.538 AC: 2652 AN: 4932

European-Non Finnish (NFE) AF: 0.655 AC: 583741 AN: 891450

Other (OTH) AF: 0.564 AC: 28797 AN: 51042

GnomAD4 genome AF: 0.467 AC: 71038 AN: 152106 Hom.: 20541 Cov.: 32 AF XY: 0.463 AC XY: 34406 AN XY: 74354

African (AFR) AF: 0.138 AC: 5723 AN: 41506

American (AMR) AF: 0.454 AC: 6943 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2184 AN: 3466

East Asian (EAS) AF: 0.239 AC: 1228 AN: 5148

South Asian (SAS) AF: 0.378 AC: 1826 AN: 4826

European-Finnish (FIN) AF: 0.635 AC: 6730 AN: 10592

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44585 AN: 67958

Other (OTH) AF: 0.516 AC: 1088 AN: 2110

Alfa AF: 0.558 Hom.: 13180

Bravo AF: 0.442

Asia WGS AF: 0.296 AC: 1030 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.73
PhyloP100		-0.41
PromoterAI		-0.063	Neutral
Mutation Taster		=130/170	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs654196; hg19: chr13-77565972;