15-68229536-C-A

Variant names:

• chr15-68229536-C-A
• rs763944821
• NM_017882.3:c.49G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017882.3(CLN6):​c.49G>T​(p.Gly17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,315,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G17S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.996
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32211936).

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.49G>T	p.Gly17Cys	missense	Exon 1 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.180-10886G>T		intron	N/A	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.49G>T	p.Gly17Cys	missense	Exon 1 of 7	ENSP00000249806.5	Q9NWW5-1
	CLN6	ENST00000637667.1	TSL:1	c.49G>T	p.Gly17Cys	missense	Exon 1 of 6	ENSP00000489843.1	A0A1B0GTU6
	CLN6	ENST00000566347.5	TSL:1	c.49G>T	p.Gly17Cys	missense	Exon 1 of 6	ENSP00000457783.1	H3BUT1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1315828 Hom.: 0 Cov.: 31 AF XY: 0.00000154 AC XY: 1 AN XY: 648858

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26476

American (AMR) AF: 0.00 AC: 0 AN: 27148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22928

East Asian (EAS) AF: 0.00 AC: 0 AN: 28188

South Asian (SAS) AF: 0.00 AC: 0 AN: 73256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3976

European-Non Finnish (NFE) AF: 9.55e-7 AC: 1 AN: 1046858

Other (OTH) AF: 0.00 AC: 0 AN: 54344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Uncertain	0.38
Sift	Benign	0.049	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.64	P
Vest4		0.37
MutPred		0.28		Gain of catalytic residue at P16 (P = 0.0119)
MVP		0.73
MPC		0.093
ClinPred		0.96	D
GERP RS		2.1
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.36

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: rs763944821; hg19: chr15-68521874;