rs994590268

Variant names:

• chr15-68229544-C-A
• rs994590268
• NM_017882.3:c.41G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-68229544-C-A
• chr15-68229544-C-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.41G>T​(p.Gly14Val) 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 1,316,536 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. G14D) has been classified as Uncertain significance.

• 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: 0.373
• 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, 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30249807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3	c.41G>T	p.Gly14Val	missense_variant	Exon 1 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.180-10894G>T		intron_variant	Intron 1 of 6		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.41G>T	p.Gly14Val	missense_variant	Exon 1 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.41G>T	p.Gly14Val	missense_variant	Exon 1 of 3	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1316536 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 649252

⚠️ 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: 26494

American (AMR) AF: 0.00 AC: 0 AN: 27296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22976

East Asian (EAS) AF: 0.00 AC: 0 AN: 28208

South Asian (SAS) AF: 0.00 AC: 0 AN: 73322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 9.55e-7 AC: 1 AN: 1047176

Other (OTH) AF: 0.00 AC: 0 AN: 54358

⚠️ 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;D;T;T;T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.090	D
MutationAssessor	Benign	1.2	.;L;.;.;.;.;.;.
PhyloP100		0.37
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.0	D;N;N;N;.;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.034	.;D;D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;D;.
Polyphen		0.069	.;B;.;.;.;.;.;.
Vest4		0.34
MutPred		0.21		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.69
MPC		0.11
ClinPred		0.62	D
GERP RS		1.4
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.32

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: rs994590268; hg19: chr15-68521882;