8-1774594-G-T

Position:

• chr8-1774594-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018941.4(CLN8):​c.543+2997G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,154 control chromosomes in the GnomAD database, including 52,000 homozygotes. 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: 𝑓 0.82 (52000 hom., cov: 32)
• Consequence: CLN8 NM_018941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.543+2997G>T		intron_variant		ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.543+2997G>T		intron_variant		1	NM_018941.4	P1

Frequencies

GnomAD3 genomes AF: 0.823 AC: 125183 AN: 152036 Hom.: 51943 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.793

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.809

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.823 AC: 125292 AN: 152154 Hom.: 52000 Cov.: 32 AF XY: 0.819 AC XY: 60956 AN XY: 74390

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.818

Gnomad4 OTH AF: 0.810

Alfa AF: 0.827 Hom.: 6509

Bravo AF: 0.812

Asia WGS AF: 0.786 AC: 2734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.76
DANN	Benign	0.56

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: rs7008465; hg19: chr8-1722760;