15-68214373-C-G

Variant names:

• chr15-68214373-C-G
• rs104894483
• NM_017882.3:c.214G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017882.3(CLN6):​c.214G>C​(p.Glu72Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,613,736 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E72K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.88
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013344973).
• BP6: Variant 15-68214373-C-G is Benign according to our data. Variant chr15-68214373-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00162 (247/152338) while in subpopulation SAS AF = 0.0129 (62/4824). AF 95% confidence interval is 0.0103. There are 3 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.214G>C	p.Glu72Gln	missense	Exon 3 of 7	NP_060352.1
	CLN6	NM_001411068.1		c.310G>C	p.Glu104Gln	missense	Exon 3 of 7	NP_001397997.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	ENST00000249806.11	TSL:1 MANE Select	c.214G>C	p.Glu72Gln	missense	Exon 3 of 7	ENSP00000249806.5
	CLN6	ENST00000566347.5	TSL:1	c.214G>C	p.Glu72Gln	missense	Exon 3 of 6	ENSP00000457783.1
	CLN6	ENST00000638076.1	TSL:1	n.214G>C		non_coding_transcript_exon	Exon 3 of 7	ENSP00000490373.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152220 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00262 AC: 659 AN: 251428 AF XY: 0.00331

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461398 Hom.: 29 Cov.: 30 AF XY: 0.00171 AC XY: 1243 AN XY: 727036

African (AFR) AF: 0.00454 AC: 152 AN: 33470

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.0163 AC: 1405 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1111608

Other (OTH) AF: 0.00167 AC: 101 AN: 60374

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152338 Hom.: 3 Cov.: 33 AF XY: 0.00191 AC XY: 142 AN XY: 74492

African (AFR) AF: 0.00406 AC: 169 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.00150

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis (2)
-	-	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	0.10
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.091
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.61
Sift	Benign	0.20	T
Sift4G	Uncertain	0.059	T
Polyphen		0.0030	B
Vest4		0.33
MVP		0.95
MPC		0.85
ClinPred		0.037	T
GERP RS		4.4
Varity_R		0.077
gMVP		0.78
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs104894483; hg19: chr15-68506711;