8-142664510-C-T

Variant names:

• chr8-142664510-C-T
• NM_003724.4:c.1549G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003724.4(JRK):​c.1549G>A​(p.Ala517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JRK NM_003724.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.354

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15901369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JRK	NM_003724.4	c.1549G>A	p.Ala517Thr	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.1549G>A	p.Ala517Thr	missense_variant	Exon 2 of 2	2	NM_003724.4	ENSP00000482410.1
JRK	ENST00000614134.1	c.1549G>A	p.Ala517Thr	missense_variant	Exon 2 of 2	1		ENSP00000485390.1
JRK	ENST00000571961.7	c.1549G>A	p.Ala517Thr	missense_variant	Exon 2 of 3	1		ENSP00000461610.1
JRK	ENST00000615982.4	c.1549G>A	p.Ala517Thr	missense_variant	Exon 2 of 4	1		ENSP00000483808.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1549G>A (p.A517T) 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 1549, causing the alanine (A) at amino acid position 517 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.3
DANN	Benign	0.68
DEOGEN2	Benign	0.0095	.;.;T;T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.51	.;T;.;T
MetaRNN	Benign	0.16	T;T;T;T
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.56	T;T;T;T
Vest4		0.14
MVP		0.35
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.016
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-143745927;