15-68229580-T-C

Variant names:

• chr15-68229580-T-C
• rs3743088
• NM_017882.3:c.5A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_017882.3(CLN6):​c.5A>G​(p.Glu2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,465,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 0.797
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P
• ceroid lipofuscinosis, neuronal, 6B (Kufs type)

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_017882.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012577295).
• BP6: Variant 15-68229580-T-C is Benign according to our data. Variant chr15-68229580-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205179.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000533 (81/151966) while in subpopulation EAS AF = 0.0114 (59/5160). AF 95% confidence interval is 0.0091. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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.5A>G	p.Glu2Gly	missense	Exon 1 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.180-10930A>G		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.5A>G	p.Glu2Gly	missense	Exon 1 of 7	ENSP00000249806.5	Q9NWW5-1
	CLN6	ENST00000637667.1	TSL:1	c.5A>G	p.Glu2Gly	missense	Exon 1 of 6	ENSP00000489843.1	A0A1B0GTU6
	CLN6	ENST00000566347.5	TSL:1	c.5A>G	p.Glu2Gly	missense	Exon 1 of 6	ENSP00000457783.1	H3BUT1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 151858 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000324 AC: 26 AN: 80306 AF XY: 0.000283

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000425

GnomAD4 exome AF: 0.000182 AC: 239 AN: 1313090 Hom.: 0 Cov.: 31 AF XY: 0.000184 AC XY: 119 AN XY: 647624

African (AFR) AF: 0.0000756 AC: 2 AN: 26458

American (AMR) AF: 0.0000371 AC: 1 AN: 26960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22894

East Asian (EAS) AF: 0.00646 AC: 179 AN: 27724

South Asian (SAS) AF: 0.000150 AC: 11 AN: 73104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4148

European-Non Finnish (NFE) AF: 0.0000124 AC: 13 AN: 1044972

Other (OTH) AF: 0.000609 AC: 33 AN: 54160

GnomAD4 genome AF: 0.000533 AC: 81 AN: 151966 Hom.: 0 Cov.: 34 AF XY: 0.000633 AC XY: 47 AN XY: 74308

African (AFR) AF: 0.000434 AC: 18 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67926

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000676

ExAC AF: 0.0000809 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis (2)
-	1	-	Ceroid lipofuscinosis, neuronal, 6A (1)
-	1	-	Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type) (1)
-	-	1	Ceroid lipofuscinosis, neuronal, 6B (Kufs type) (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.80
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.24	B
Vest4		0.39
MVP		0.88
MPC		0.10
ClinPred		0.079	T
GERP RS		3.3
PromoterAI		-0.21	Neutral
Varity_R		0.13
gMVP		0.27
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743088; hg19: chr15-68521918;