8-142664725-C-T

Variant names:

• chr8-142664725-C-T
• NM_003724.4:c.1334G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003724.4(JRK):​c.1334G>A​(p.Arg445Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R445M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JRK NM_003724.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.419

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064727515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JRK	NM_003724.4	c.1334G>A	p.Arg445Lys	missense_variant	Exon 2 of 2	ENST00000612905.2	NP_003715.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JRK	ENST00000612905.2	c.1334G>A	p.Arg445Lys	missense_variant	Exon 2 of 2	2	NM_003724.4	ENSP00000482410.1
JRK	ENST00000614134.1	c.1334G>A	p.Arg445Lys	missense_variant	Exon 2 of 2	1		ENSP00000485390.1
JRK	ENST00000571961.7	c.1334G>A	p.Arg445Lys	missense_variant	Exon 2 of 3	1		ENSP00000461610.1
JRK	ENST00000615982.4	c.1334G>A	p.Arg445Lys	missense_variant	Exon 2 of 4	1		ENSP00000483808.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450630 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 720476

Gnomad4 AFR exome AF: 0.00

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: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1334G>A (p.R445K) alteration is located in exon 2 (coding exon 1) of the JRK gene. This alteration results from a G to A substitution at nucleotide position 1334, causing the arginine (R) at amino acid position 445 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.29
DANN	Benign	0.67
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.32	.;T;.;T
MetaRNN	Benign	0.065	T;T;T;T
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.93	T;T;T;T
Vest4		0.044
MVP		0.24
GERP RS		-1.9
Varity_R		0.032
gMVP		0.19

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: chr8-143746144;