chr15-68229568-C-G

Variant names:

• chr15-68229568-C-G
• rs154774636
• NM_017882.3:c.17G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_017882.3(CLN6):​c.17G>C​(p.Arg6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,315,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.370
• Publications: 6 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• ceroid lipofuscinosis, neuronal, 6B (Kufs type)

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-68229568-C-G is Pathogenic according to our data. Variant chr15-68229568-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30602.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	NM_017882.3	MANE Select	c.17G>C	p.Arg6Thr	missense	Exon 1 of 7	NP_060352.1
	CLN6	NM_001411068.1		c.180-10918G>C		intron	N/A	NP_001397997.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	ENST00000249806.11	TSL:1 MANE Select	c.17G>C	p.Arg6Thr	missense	Exon 1 of 7	ENSP00000249806.5
	CLN6	ENST00000637667.1	TSL:1	c.17G>C	p.Arg6Thr	missense	Exon 1 of 6	ENSP00000489843.1
	CLN6	ENST00000566347.5	TSL:1	c.17G>C	p.Arg6Thr	missense	Exon 1 of 6	ENSP00000457783.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000123 AC: 1 AN: 81494 AF XY: 0.0000215

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000228 AC: 3 AN: 1315504 Hom.: 0 Cov.: 31 AF XY: 0.00000308 AC XY: 2 AN XY: 648824

⚠️ 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: 26504

American (AMR) AF: 0.00 AC: 0 AN: 27244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22964

East Asian (EAS) AF: 0.00 AC: 0 AN: 27956

South Asian (SAS) AF: 0.00 AC: 0 AN: 73282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000287 AC: 3 AN: 1046430

Other (OTH) AF: 0.00 AC: 0 AN: 54310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Pathogenic:1

May 13, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Other:1

SNPedia

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.37
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.36
MutPred		0.20		Loss of MoRF binding (P = 0.0149)
MVP		0.86
MPC		0.13
ClinPred		0.96	D
GERP RS		2.4
PromoterAI		0.093	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
gMVP		0.36
Mutation Taster		=17/83	disease causing (ClinVar)

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: rs154774636; hg19: chr15-68521906;