8-1771440-G-T

Position:

• chr8-1771440-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_018941.4(CLN8):​c.386G>T​(p.Arg129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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 Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.37285107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.386G>T	p.Arg129Leu	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.386G>T	p.Arg129Leu	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.386G>T		non_coding_transcript_exon_variant	2/30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;D;D;D;.;D;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;.;.;.;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.1	.;M;M;M;M;.;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.4	.;D;.;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.075	.;T;.;.;.;.;.;.
Sift4G	Benign	0.22	.;T;.;.;.;.;.;T
Polyphen		0.84	.;P;P;P;P;.;P;.
Vest4		0.55
MutPred		0.55		Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);Loss of catalytic residue at R129 (P = 0.01);
MVP		0.86
MPC		0.055
ClinPred		0.79	D
GERP RS		-0.16
Varity_R		0.23
gMVP		0.58

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: rs571617007; hg19: chr8-1719606;