chr8-142664551-C-T

Variant names:

• chr8-142664551-C-T
• rs35283248
• NM_003724.4:c.1508G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003724.4(JRK):​c.1508G>A​(p.Arg503Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,607,948 control chromosomes in the GnomAD database, including 69 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (64 hom.)
• Consequence: JRK NM_003724.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037443936).
• BP6: Variant 8-142664551-C-T is Benign according to our data. Variant chr8-142664551-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 779431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 gene

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.1508G>A	p.Arg503Gln	missense	Exon 2 of 2	NP_003715.3	O75564-2
	JRK	NM_001077527.3		c.1508G>A	p.Arg503Gln	missense	Exon 2 of 3	NP_001070995.2	O75564-1
	JRK	NM_001279352.2		c.1508G>A	p.Arg503Gln	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.1508G>A	p.Arg503Gln	missense	Exon 2 of 2	ENSP00000482410.1	O75564-2
	JRK	ENST00000614134.1	TSL:1	c.1508G>A	p.Arg503Gln	missense	Exon 2 of 2	ENSP00000485390.1	O75564-2
	JRK	ENST00000571961.7	TSL:1	c.1508G>A	p.Arg503Gln	missense	Exon 2 of 3	ENSP00000461610.1	O75564-1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152194 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00841

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00573 AC: 1329 AN: 231884 AF XY: 0.00575

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00930

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00804 AC: 11701 AN: 1455636 Hom.: 64 Cov.: 35 AF XY: 0.00775 AC XY: 5611 AN XY: 723892

African (AFR) AF: 0.00108 AC: 36 AN: 33358

American (AMR) AF: 0.00109 AC: 48 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 26 AN: 25960

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39514

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85402

European-Finnish (FIN) AF: 0.0139 AC: 712 AN: 51160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00947 AC: 10517 AN: 1110100

Other (OTH) AF: 0.00599 AC: 360 AN: 60144

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152312 Hom.: 5 Cov.: 33 AF XY: 0.00473 AC XY: 352 AN XY: 74470

African (AFR) AF: 0.00171 AC: 71 AN: 41584

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00841 AC: 572 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00693 Hom.: 6

Bravo AF: 0.00457

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.000939 AC: 4

ESP6500EA AF: 0.00860 AC: 73

ExAC AF: 0.00595 AC: 718

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.10
DANN	Benign	0.83
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0037	T
PhyloP100		-1.8
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.91	T
Vest4		0.021
MVP		0.32
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.089

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: rs35283248; hg19: chr8-143745968;