8-142664882-C-G

Variant names:

• chr8-142664882-C-G
• rs782664346
• NM_003724.4:c.1177G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003724.4(JRK):​c.1177G>C​(p.Glu393Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,194,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign 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. E393K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: JRK NM_003724.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.919
• Publications: 0 publications found

Genes affected

JRK (HGNC:6199): (Jrk helix-turn-helix protein) This gene encodes a conserved protein that is similar to DNA-binding proteins, such as major centromere autoantigen B (CENPB). Inactivation of the related gene in mice resulted in epileptic seizures. Childhood Absence Epilepsy (CAE) has been mapped to the same chromosomal location (8q24.3) as this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.115991235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003724.4. 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
	JRK	NM_003724.4	MANE Select	c.1177G>C	p.Glu393Gln	missense	Exon 2 of 2	NP_003715.3	O75564-2
	JRK	NM_001077527.3		c.1177G>C	p.Glu393Gln	missense	Exon 2 of 3	NP_001070995.2	O75564-1
	JRK	NM_001279352.2		c.1177G>C	p.Glu393Gln	missense	Exon 2 of 4	NP_001266281.1	O75564-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JRK	ENST00000612905.2	TSL:2 MANE Select	c.1177G>C	p.Glu393Gln	missense	Exon 2 of 2	ENSP00000482410.1	O75564-2
	JRK	ENST00000614134.1	TSL:1	c.1177G>C	p.Glu393Gln	missense	Exon 2 of 2	ENSP00000485390.1	O75564-2
	JRK	ENST00000571961.7	TSL:1	c.1177G>C	p.Glu393Gln	missense	Exon 2 of 3	ENSP00000461610.1	O75564-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000167 AC: 2 AN: 1194558 Hom.: 0 Cov.: 17 AF XY: 0.00000331 AC XY: 2 AN XY: 604544

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28212

American (AMR) AF: 0.00 AC: 0 AN: 43614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24280

East Asian (EAS) AF: 0.00 AC: 0 AN: 38178

South Asian (SAS) AF: 0.00 AC: 0 AN: 79958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5254

European-Non Finnish (NFE) AF: 0.00000229 AC: 2 AN: 872168

Other (OTH) AF: 0.00 AC: 0 AN: 51422

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.71
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.12	T
PhyloP100		0.92
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.068	T
Vest4		0.058
MVP		0.27
GERP RS		2.8
Varity_R		0.086
gMVP		0.30

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: rs782664346; hg19: chr8-143746301;