rs386833708

chr16-28491759-T-Cchr16-28491759-T-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001042432.2(CLN3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLN3 NM_001042432.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001042432.2 (CLN3) was described as [Likely_pathogenic] in ClinVar as 371317
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-28491759-T-C is Pathogenic according to our data. Variant chr16-28491759-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1A>G	p.Met1?	start_lost	2/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1A>G	p.Met1?	start_lost	2/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250966 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 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: 0.0000894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. This variant is present in population databases (rs386833708, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with Neuronal ceroid lipofuscinosis and/or retinitis pigmentosa (PMID: 32154056; Invitae). ClinVar contains an entry for this variant (Variation ID: 550268). For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 27, 2016

- -

CLN3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2023

The CLN3 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has not been reported in the literature, however other variant c.1A>C disrupting initiation codon has been reported in compound heterozygous state in three individuals with attenuated form of CLN3 disease (Kuper et al 2020. PubMed ID: 32154056). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-28503080-T-C). In summary, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.75	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	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.86, 0.92, 0.98, 0.63	.;P;P;.;.;.;.;P;P;D;.;P;.;.;.;.
Vest4		0.70, 0.81, 0.81, 0.76, 0.82, 0.78, 0.61
MutPred		1.0		Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);
MVP		0.93
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;