rs751562146

Variant names:

• chr15-68209668-G-A
• rs751562146
• NM_017882.3:c.634C>T

Variant summary

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

The NM_017882.3(CLN6):​c.634C>T​(p.Leu212Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L212P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35
• Publications: 0 publications found

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]

CLN6 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 6A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• ceroid lipofuscinosis, neuronal, 6B (Kufs type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	NM_017882.3	MANE Select	c.634C>T	p.Leu212Phe	missense	Exon 6 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.730C>T	p.Leu244Phe	missense	Exon 6 of 7	NP_001397997.1	Q9NWW5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	ENST00000249806.11	TSL:1 MANE Select	c.634C>T	p.Leu212Phe	missense	Exon 6 of 7	ENSP00000249806.5	Q9NWW5-1
	CLN6	ENST00000637667.1	TSL:1	c.535C>T	p.Leu179Phe	missense	Exon 5 of 6	ENSP00000489843.1	A0A1B0GTU6
	CLN6	ENST00000566347.5	TSL:1	c.445C>T	p.Leu149Phe	missense	Exon 5 of 6	ENSP00000457783.1	H3BUT1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251326 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461152 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726884

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.089
BayesDel_addAF	Benign	0.0083	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.59
Sift	Benign	0.17	T
Sift4G	Benign	0.065	T
Polyphen		0.92	P
Vest4		0.59
MutPred		0.32		Gain of catalytic residue at L244 (P = 0.1172)
MVP		0.95
MPC		0.91
ClinPred		0.55	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.75
Mutation Taster		=68/32	polymorphism

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: rs751562146; hg19: chr15-68502006;