NM_001261833.2:c.407G>A

Variant names:

• chr11-96391056-G-A
• rs1473171837
• NM_001261833.2:c.407G>A

Variant summary

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

The NM_001261833.2(JRKL):​c.407G>A​(p.Arg136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JRKL NM_001261833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 publications found

Genes affected

JRKL (HGNC:6200): (JRK like) The function of this gene has not yet been defined, however, the encoded protein shares similarity with the human (41% identical) and mouse (34% identical) jerky gene products. This protein may act as a nuclear regulatory protein. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

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=0.16415527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JRKL	NM_001261833.2	c.407G>A	p.Arg136Lys	missense_variant	Exon 2 of 2	ENST00000332349.5	NP_001248762.1
JRKL	NM_003772.4	c.407G>A	p.Arg136Lys	missense_variant	Exon 1 of 1		NP_003763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JRKL	ENST00000332349.5	c.407G>A	p.Arg136Lys	missense_variant	Exon 2 of 2	2	NM_001261833.2	ENSP00000333350.4
JRKL	ENST00000546177.1	n.85+983G>A		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250632 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407G>A (p.R136K) alteration is located in exon 1 (coding exon 1) of the JRKL gene. This alteration results from a G to A substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		2.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.093
Sift	Benign	0.85	T
Sift4G	Benign	0.93	T
Polyphen		0.83	P
Vest4		0.15
MutPred		0.38		Gain of methylation at R136 (P = 0.0271);
MVP		0.42
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.54
Mutation Taster		=91/9	polymorphism

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: rs1473171837; hg19: chr11-96124220;