NM_001042432.2:c.776C>A

Variant names:

• chr16-28484020-G-T
• rs137858807
• NM_001042432.2:c.776C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042432.2(CLN3):​c.776C>A​(p.Pro259Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P259L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 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: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3199332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.776C>A	p.Pro259Gln	missense_variant	Exon 10 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.776C>A	p.Pro259Gln	missense_variant	Exon 10 of 16	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456972 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724270

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109750

Other (OTH) AF: 0.00 AC: 0 AN: 60190

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Aug 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with glutamine at codon 259 of the CLN3 protein (p.Pro259Gln). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Uncertain	0.60	.;D;D;.;.;T;.;.;D;D;T;.;D;.;.;.;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;.;.;T;.;.;T;T;T;.;T;T;T;.;T;T;T;T;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.7	.;L;L;.;.;.;.;.;.;L;.;L;.;.;.;.;.;.;.
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	.;.;N;.;.;N;N;N;.;N;.;N;.;.;N;.;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.069	.;.;T;.;.;T;T;T;.;T;.;T;.;.;T;.;T;.;D
Sift4G	Benign	0.28	.;.;.;T;.;T;T;T;.;T;.;T;.;.;.;.;T;.;.
Polyphen		0.020, 0.0030, 0.089, 0.023, 0.017, 0.16	.;B;B;.;.;B;.;.;.;B;B;B;B;.;B;.;B;.;.
Vest4		0.21, 0.20, 0.24, 0.22, 0.20, 0.32
MutPred		0.39		Loss of glycosylation at P259 (P = 0.0106);Loss of glycosylation at P259 (P = 0.0106);Loss of glycosylation at P259 (P = 0.0106);Loss of glycosylation at P259 (P = 0.0106);.;.;.;.;.;Loss of glycosylation at P259 (P = 0.0106);.;Loss of glycosylation at P259 (P = 0.0106);.;.;.;.;.;.;.;
MVP		0.94
MPC		0.16
ClinPred		0.25	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
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

Other links and lift over

dbSNP: rs137858807; hg19: chr16-28495341;