chr13-76992023-A-G

Variant names:

• chr13-76992023-A-G
• rs7987664
• ENST00000636183.2:c.-76A>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.-76A>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 0.0485 in 1,606,282 control chromosomes in the GnomAD database, including 3,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (785 hom., cov: 33)
  • Exomes 𝑓: 0.045 (2283 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.43
• Publications: 8 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=-0.75).
• BP6: Variant 13-76992023-A-G is Benign according to our data. Variant chr13-76992023-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 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.-76A>G		upstream_gene	N/A	NP_006484.2
	CLN5	NM_001366624.2		c.-76A>G		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.-76A>G		5_prime_UTR	Exon 1 of 4	ENSP00000490181.2
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-76A>G		upstream_gene	N/A	ENSP00000366673.5
	ENSG00000283208	ENST00000638147.2	TSL:5	c.-76A>G		upstream_gene	N/A	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12477 AN: 152126 Hom.: 788 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0717 AC: 15940 AN: 222188 AF XY: 0.0638

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0450 AC: 65399 AN: 1454040 Hom.: 2283 Cov.: 35 AF XY: 0.0441 AC XY: 31855 AN XY: 723108

African (AFR) AF: 0.160 AC: 5327 AN: 33350

American (AMR) AF: 0.162 AC: 7174 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 1070 AN: 25974

East Asian (EAS) AF: 0.126 AC: 4973 AN: 39522

South Asian (SAS) AF: 0.0524 AC: 4487 AN: 85656

European-Finnish (FIN) AF: 0.0356 AC: 1774 AN: 49876

Middle Eastern (MID) AF: 0.0472 AC: 260 AN: 5506

European-Non Finnish (NFE) AF: 0.0336 AC: 37331 AN: 1110022

Other (OTH) AF: 0.0501 AC: 3003 AN: 59978

GnomAD4 genome AF: 0.0821 AC: 12499 AN: 152242 Hom.: 785 Cov.: 33 AF XY: 0.0827 AC XY: 6156 AN XY: 74444

African (AFR) AF: 0.160 AC: 6647 AN: 41552

American (AMR) AF: 0.119 AC: 1818 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3470

East Asian (EAS) AF: 0.138 AC: 711 AN: 5156

South Asian (SAS) AF: 0.0526 AC: 254 AN: 4826

European-Finnish (FIN) AF: 0.0385 AC: 409 AN: 10612

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0337 AC: 2290 AN: 68008

Other (OTH) AF: 0.0695 AC: 147 AN: 2114

Alfa AF: 0.0441 Hom.: 134

Bravo AF: 0.0924

Asia WGS AF: 0.105 AC: 364 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		-1.4
PromoterAI		-0.14	Neutral
Mutation Taster		=100/0	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: rs7987664; hg19: chr13-77566158; COSMIC: COSV66284915; COSMIC: COSV66284915;