rs779456928

Positions:

• chr15-68218618-C-A
• chr15-68218618-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017882.3(CLN6):​c.116G>T​(p.Arg39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.688

Genes affected

CLN6 (HGNC:2077): (CLN6 transmembrane ER protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15572518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3	c.116G>T	p.Arg39Leu	missense_variant	2/7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.212G>T	p.Arg71Leu	missense_variant	2/7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.116G>T	p.Arg39Leu	missense_variant	2/7	1	NM_017882.3	ENSP00000249806	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251258 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461506 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.53
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.83	D;D;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	T;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.7	D;D;D;.;.;D
REVEL	Benign	0.15
Sift	Benign	0.14	T;D;T;.;.;T
Sift4G	Benign	0.37	T;T;T;.;.;T
Polyphen		0.15	B;.;.;.;.;.
Vest4		0.19
MutPred		0.31		.;.;Loss of disorder (P = 0.0374);.;.;.;
MVP		0.82
MPC		0.39
ClinPred		0.11	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.079
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs779456928; hg19: chr15-68510956;