1-160042148-T-C

Variant names:

• chr1-160042148-T-C
• rs751625111
• NM_002241.5:c.385A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002241.5(KCNJ10):​c.385A>G​(p.Ile129Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000183 in 1,584,356 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ10	NM_002241.5	c.385A>G	p.Ile129Val	missense_variant	Exon 2 of 2	ENST00000644903.1	NP_002232.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1	c.385A>G	p.Ile129Val	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151992 Hom.: 0 Cov.: 32

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 AF: 0.0000195 AC: 28 AN: 1432364 Hom.: 0 Cov.: 32 AF XY: 0.0000169 AC XY: 12 AN XY: 708746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000237

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

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

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome;C2748572:EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Sep 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EAST syndrome Uncertain:1

Jun 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 129 of the KCNJ10 protein (p.Ile129Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SeSAME/EAST syndrome (PMID: 22612257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 582279). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;D;D;.;D;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;.;D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;.;M;M;.;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.95	.;.;.;N;.;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.042	.;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.
Polyphen		1.0	.;.;D;D;.;D;D
Vest4		0.42
MVP		0.80
MPC		1.3
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.96

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

Other links and lift over

dbSNP: rs751625111; hg19: chr1-160011938;