rs386834125

Positions:

• chr8-1771281-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_018941.4(CLN8):​c.227A>G​(p.Gln76Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.66

Genes affected

CLN8 (HGNC:2079): (CLN8 transmembrane ER and ERGIC protein) This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]

KBTBD11-OT1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain TLC (size 200) in uniprot entity CLN8_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 8-1771281-A-G is Pathogenic according to our data. Variant chr8-1771281-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56705.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-1771281-A-G is described in UniProt as null. Variant chr8-1771281-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.227A>G	p.Gln76Arg	missense_variant	2/3	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.227A>G	p.Gln76Arg	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.227A>G		non_coding_transcript_exon_variant	2/30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T;.;.;.;.;T;.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.6	.;M;M;M;M;.;M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Benign	0.089	.;T;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;T;.;.;.;.;.;D;.
Polyphen		1.0	.;D;D;D;D;.;D;.;.
Vest4		0.87
MutPred		0.75		Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);Gain of methylation at Q76 (P = 0.0101);
MVP		0.95
MPC		0.26
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834125; hg19: chr8-1719447;