8-1771469-C-A

Variant names:

• chr8-1771469-C-A
• NM_018941.4:c.415C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_018941.4(CLN8):​c.415C>A​(p.His139Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H139Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29

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 6 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, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.415C>A	p.His139Asn	missense_variant	Exon 2 of 3	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.415C>A	p.His139Asn	missense_variant	Exon 2 of 3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.415C>A		non_coding_transcript_exon_variant	Exon 2 of 30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;D;D;.;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;.;.;.;T;.;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;M;M;M;.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;.;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.011	D;.;.;.;.;.;.
Sift4G	Uncertain	0.029	D;.;.;.;.;.;D
Polyphen		1.0	D;D;D;D;.;D;.
Vest4		0.96
MutPred		0.76		Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);Gain of helix (P = 0.0861);
MVP		0.96
MPC		0.29
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.43
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-1719635;