13-76991955-C-T

Variant names:

• chr13-76991955-C-T
• rs77416795
• ENST00000636183.2:c.-144C>T

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.-144C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,563,562 control chromosomes in the GnomAD database, including 12,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11016 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.316
• Publications: 17 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 (MetaRNN=0.004951477).
• BP6: Variant 13-76991955-C-T is Benign according to our data. Variant chr13-76991955-C-T is described in ClinVar as Benign. ClinVar VariationId is 128782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

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.-144C>T		upstream_gene	N/A	NP_006484.2
	CLN5	NM_001366624.2		c.-144C>T		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.-144C>T		5_prime_UTR	Exon 1 of 4	ENSP00000490181.2
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-144C>T		upstream_gene	N/A	ENSP00000366673.5
	ENSG00000283208	ENST00000638147.2	TSL:5	c.-144C>T		upstream_gene	N/A	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19446 AN: 152048 Hom.: 1361 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.0887

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.145 AC: 23394 AN: 160952 AF XY: 0.139

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.0942

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.121 AC: 171247 AN: 1411396 Hom.: 11016 Cov.: 35 AF XY: 0.121 AC XY: 84441 AN XY: 699018

African (AFR) AF: 0.142 AC: 4618 AN: 32530

American (AMR) AF: 0.272 AC: 10487 AN: 38574

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 2315 AN: 25360

East Asian (EAS) AF: 0.111 AC: 4144 AN: 37184

South Asian (SAS) AF: 0.130 AC: 10586 AN: 81484

European-Finnish (FIN) AF: 0.102 AC: 4148 AN: 40574

Middle Eastern (MID) AF: 0.112 AC: 629 AN: 5594

European-Non Finnish (NFE) AF: 0.117 AC: 127258 AN: 1091356

Other (OTH) AF: 0.120 AC: 7062 AN: 58740

GnomAD4 genome AF: 0.128 AC: 19457 AN: 152166 Hom.: 1362 Cov.: 33 AF XY: 0.128 AC XY: 9498 AN XY: 74416

African (AFR) AF: 0.137 AC: 5672 AN: 41512

American (AMR) AF: 0.207 AC: 3175 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 308 AN: 3472

East Asian (EAS) AF: 0.121 AC: 628 AN: 5172

South Asian (SAS) AF: 0.126 AC: 607 AN: 4824

European-Finnish (FIN) AF: 0.109 AC: 1151 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7608 AN: 67970

Other (OTH) AF: 0.114 AC: 240 AN: 2108

Alfa AF: 0.114 Hom.: 1725

Bravo AF: 0.136

TwinsUK AF: 0.112 AC: 416

ALSPAC AF: 0.118 AC: 455

ESP6500AA AF: 0.113 AC: 400

ESP6500EA AF: 0.101 AC: 731

ExAC AF: 0.106 AC: 11817

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis (2)
-	-	2	Neuronal ceroid lipofuscinosis 5 (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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.32
PrimateAI	Uncertain	0.58	T
ClinPred		0.099	T
GERP RS		2.1
PromoterAI		0.080	Neutral
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: rs77416795; hg19: chr13-77566090; COSMIC: COSV66283779; COSMIC: COSV66283779;