rs73533466

Variant names:

• chr16-28484025-C-A
• rs73533466
• NM_001042432.2:c.771G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-28484025-C-A
• chr16-28484025-C-G
• chr16-28484025-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042432.2(CLN3):​c.771G>T​(p.Glu257Asp) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E257K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19726744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042432.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	NM_001042432.2	MANE Select	c.771G>T	p.Glu257Asp	missense	Exon 10 of 16	NP_001035897.1
	CLN3	NM_000086.2		c.771G>T	p.Glu257Asp	missense	Exon 9 of 15	NP_000077.1
	CLN3	NM_001286104.2		c.699G>T	p.Glu233Asp	missense	Exon 9 of 15	NP_001273033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.771G>T	p.Glu257Asp	missense	Exon 10 of 16	ENSP00000490105.1
	CLN3	ENST00000359984.12	TSL:1	c.771G>T	p.Glu257Asp	missense	Exon 9 of 15	ENSP00000353073.9
	CLN3	ENST00000565316.6	TSL:1	c.771G>T	p.Glu257Asp	missense	Exon 9 of 14	ENSP00000456117.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.3
DANN	Benign	0.83
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.4	L
PhyloP100		-0.13
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.34
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Polyphen		0.043	B
Vest4		0.29
MutPred		0.51		Loss of glycosylation at P259 (P = 0.0891)
MVP		0.89
MPC		0.23
ClinPred		0.29	T
GERP RS		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.24

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: rs73533466; hg19: chr16-28495346;