chr8-1771142-G-C

Position:

• chr8-1771142-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_018941.4(CLN8):​c.88G>C​(p.Ala30Pro) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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, 10 uncertain in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• PP5: Variant 8-1771142-G-C is Pathogenic according to our data. Variant chr8-1771142-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2806.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-1771142-G-C is described in UniProt as null. Variant chr8-1771142-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.88G>C	p.Ala30Pro	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.88G>C	p.Ala30Pro	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;D;D;D;.;D;.;.
Eigen	Benign	0.053
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;.;.;.;.;T;.;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;.;M;.;.
MutationTaster	Benign	0.98	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	.;D;.;.;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Benign	0.059	.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.11	T;T;.;.;.;.;.;T;.
Polyphen		0.96	.;P;P;P;P;.;P;.;.
Vest4		0.93
MutPred		0.67		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.93
MPC		0.24
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.59
gMVP		0.88

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: rs137852883; hg19: chr8-1719308;