chr16-28491759-T-G

Position:

• chr16-28491759-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_001042432.2(CLN3):​c.1A>C​(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 0.00000137 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_001042432.2 start_lost
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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-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/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1A>C	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>C	p.Met1?	start_lost	2/16	1	NM_001042432.2	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56257). 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). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. -

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

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

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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
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
MutationTaster	Benign	1.0	D;D;D;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;