16-28491759-T-G

Variant names:

• chr16-28491759-T-G
• rs386833708
• ENST00000636228.1:c.-83A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001286110.2(CLN3):​c.-83A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLN3 NM_001286110.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.17
• Publications: 6 publications found

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 16-28491759-T-G is Pathogenic according to our data. Variant chr16-28491759-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 56257.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286110.2. 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
	CLN3	NM_001042432.2	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 2 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_001286110.2		c.-83A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001273039.1	B4DFF3
	CLN3	NM_001286109.2		c.-83A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001273038.1	Q2TA70

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636228.1	TSL:1	c.-83A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000489627.1	O95086
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 2 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 15	ENSP00000353073.9	Q13286-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neuronal ceroid lipofuscinosis (1)
1	-	-	Neuronal ceroid lipofuscinosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
PhyloP100		2.2
PROVEAN	Benign	-0.63	N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.73	P
Vest4		0.73
MutPred		1.0		Loss of MoRF binding (P = 0.0739)
MVP		0.91
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.87
gMVP		0.29
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs386833708; hg19: chr16-28503080;