16-28487469-C-T

Variant names:

• chr16-28487469-C-T
• rs779918787
• ENST00000357806.11:c.367G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000357806.11(CLN3):​c.367G>A​(p.Asp123Asn) 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D123Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN3 ENST00000357806.11 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.269
• Publications: 1 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_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06518656).
• BP6: Variant 16-28487469-C-T is Benign according to our data. Variant chr16-28487469-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2743507.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357806.11. 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.447G>A	p.Gly149Gly	synonymous	Exon 7 of 16	NP_001035897.1
	CLN3	NM_000086.2		c.447G>A	p.Gly149Gly	synonymous	Exon 6 of 15	NP_000077.1
	CLN3	NM_001286104.2		c.375G>A	p.Gly125Gly	synonymous	Exon 6 of 15	NP_001273033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000357806.11	TSL:1	c.367G>A	p.Asp123Asn	missense	Exon 5 of 12	ENSP00000350457.7
	CLN3	ENST00000565778.6	TSL:1	c.295G>A	p.Asp99Asn	missense	Exon 4 of 7	ENSP00000458015.1
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.447G>A	p.Gly149Gly	synonymous	Exon 7 of 16	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	5.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.065	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		0.27
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.14
Sift	Benign	0.076	T
Sift4G	Benign	0.57	T
Polyphen		0.011	B
Vest4		0.27
MutPred		0.21		Gain of sheet (P = 0.1208)
MVP		0.70
ClinPred		0.077	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs779918787; hg19: chr16-28498790;