8-1771263-G-C

Variant names:

• chr8-1771263-G-C
• rs386834124
• NM_018941.4:c.209G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_018941.4(CLN8):​c.209G>C​(p.Arg70Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.28
• Publications: 0 publications found

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]

CLN8 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neuronal ceroid lipofuscinosis 8 northern epilepsy variant

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-1771262-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 242453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 8-1771263-G-C is Pathogenic according to our data. Variant chr8-1771263-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1063566.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	NM_018941.4	MANE Select	c.209G>C	p.Arg70Pro	missense	Exon 2 of 3	NP_061764.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	ENST00000331222.6	TSL:1 MANE Select	c.209G>C	p.Arg70Pro	missense	Exon 2 of 3	ENSP00000328182.4	Q9UBY8
	KBTBD11-OT1	ENST00000635855.1	TSL:5	n.209G>C		non_coding_transcript_exon	Exon 2 of 30	ENSP00000489726.1	A0A1B0GTJ5
	CLN8	ENST00000519254.2	TSL:5	c.209G>C	p.Arg70Pro	missense	Exon 2 of 3	ENSP00000490016.1	Q9UBY8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronal ceroid lipofuscinosis 8 (2)
-	1	-	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.84		Loss of methylation at R70 (P = 0.0478)
MVP		0.95
MPC		0.32
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.96
Mutation Taster		=12/88	disease causing

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: rs386834124; hg19: chr8-1719429;