NM_001042432.2:c.1054C>G

Variant names:

• chr16-28482107-G-C
• rs386833697
• NM_001042432.2:c.1054C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001042432.2(CLN3):​c.1054C>G​(p.Gln352Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q352H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense, splice_region
• Scores: Splicing: ADA: 0.8983
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-28482105-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 660322.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.1054C>G	p.Gln352Glu	missense_variant, splice_region_variant	Exon 14 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.1054C>G	p.Gln352Glu	missense_variant, splice_region_variant	Exon 14 of 16	1	NM_001042432.2	ENSP00000490105.1
ENSG00000261832	ENST00000637378.1	c.226C>G	p.Gln76Glu	missense_variant, splice_region_variant	Exon 4 of 10	5		ENSP00000490831.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459710 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726002

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111244

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;D;.;D;.;.;D;D;D;.;D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;T;.;.;.;.;D;D;D;.;D;D;D;.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.4	.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	.;.;.;D;.;D;D;N;.;D;.;D;.;.;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	.;.;.;D;.;D;D;D;.;D;.;D;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;D;D;.;D;.;D;.;.;.;.
Polyphen		1.0, 1.0, 0.99	.;.;D;D;.;D;.;.;.;D;D;D;D;.;D;.
Vest4		0.83, 0.82, 0.80, 0.83, 0.79
MutPred		0.87		.;.;Loss of MoRF binding (P = 0.0651);Loss of MoRF binding (P = 0.0651);.;.;.;.;.;Loss of MoRF binding (P = 0.0651);.;.;.;.;.;.;
MVP		0.96
MPC		0.66
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.88
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.060		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: rs386833697; hg19: chr16-28493428;