chr8-142664501-C-A

Position:

• chr8-142664501-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003724.4(JRK):​c.1558G>T​(p.Ala520Ser) 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JRK NM_003724.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0180

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=0.11648393).
• BP6: Variant 8-142664501-C-A is Benign according to our data. Variant chr8-142664501-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2404278.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JRK	NM_003724.4	c.1558G>T	p.Ala520Ser	missense_variant	2/2	ENST00000612905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JRK	ENST00000612905.2	c.1558G>T	p.Ala520Ser	missense_variant	2/2	2	NM_003724.4	P2
JRK	ENST00000614134.1	c.1558G>T	p.Ala520Ser	missense_variant	2/2	1		P2
JRK	ENST00000571961.7	c.1558G>T	p.Ala520Ser	missense_variant	2/3	1		A2
JRK	ENST00000615982.4	c.1558G>T	p.Ala520Ser	missense_variant	2/4	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.043
DANN	Benign	0.60
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.12	T;T;T;T
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.88	T;T;T;T
Vest4		0.027
MVP		0.33
GERP RS		-4.5
Varity_R		0.026
gMVP		0.085

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: chr8-143745918;