chr1-160042312-G-A

Position:

chr1-160042312-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_002241.5(KCNJ10):c.221C>T(p.Thr74Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

KCNJ10 (HGNC:6256): (potassium inwardly rectifying channel subfamily J member 10) This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]

KCNJ10 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a transmembrane_region Helical; Name=M1 (size 24) in uniprot entity KCJ10_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_002241.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 1-160042312-G-A is Pathogenic according to our data. Variant chr1-160042312-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205818.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr1-160042312-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.221C>T	p.Thr74Ile	missense_variant	2/2	ENST00000644903.1	NP_002232.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1 linkuse as main transcript	c.221C>T	p.Thr74Ile	missense_variant	2/2		NM_002241.5	ENSP00000495557	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2014

p.Thr74Ile (ACC>ATC): c.221 C>T in exon 2 of the KCNJ10 gene (NM_002241.4). The T74I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T74I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals in the M1 transmembrane domain of the KCNJ10 protein and missense mutations in nearby residues (V84M, G77R, F75L) have been reported in association with epilepsy, supporting the functional importance of this region of the KCNJ10 protein. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s). -

EAST syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with KCNJ10-related disease. ClinVar contains an entry for this variant (Variation ID: 205818). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 74 of the KCNJ10 protein (p.Thr74Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;D;.;D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;.;.;D;.;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.8

.;.;M;M;.;M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.1

.;.;.;N;.;.;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

.;.;.;D;.;.;.

Sift4G

Uncertain

0.012

.;.;.;D;.;.;.

Polyphen

1.0

.;.;D;D;.;D;D

Vest4

0.49

MutPred

0.73

Loss of glycosylation at T74 (P = 0.0921);Loss of glycosylation at T74 (P = 0.0921);Loss of glycosylation at T74 (P = 0.0921);Loss of glycosylation at T74 (P = 0.0921);.;Loss of glycosylation at T74 (P = 0.0921);Loss of glycosylation at T74 (P = 0.0921);

MVP

0.83

MPC

1.5

ClinPred

0.99

GERP RS

4.2

Varity_R

0.51

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over