chr16-28491759-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ENSG00000261832 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 56257.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28491759-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 16	1	NM_001042432.2	ENSP00000490105.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Pathogenic:1

Sep 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with neuronal ceroid lipofuscinosis and may be associated with a milder phenotype (PMID: 21990111, 32154056). ClinVar contains an entry for this variant (Variation ID: 56257). For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;.;T;.;.;.;T;T;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
PROVEAN	Benign	-0.63	.;.;N;.;N;N;N;N;N;N;.;N;N;N;N;N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;.;D;.;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D;D;D;D;D;D;.;D;.;.;.;D
Polyphen		0.73, 0.83, 0.91, 0.43	.;P;P;.;.;.;.;P;P;P;.;B;.;.;.;.
Vest4		0.73, 0.82, 0.68, 0.84, 0.80, 0.55
MutPred		1.0		Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);
MVP		0.91
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.87
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833708; hg19: chr16-28503080;