NM_002241.5:c.229G>C

Variant names:

• chr1-160042304-C-G
• rs137853072
• NM_002241.5:c.229G>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_002241.5(KCNJ10):​c.229G>C​(p.Gly77Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003523914: Experimental studies have shown that this missense change affects KCNJ10 function (PMID:19420365, 20807765, 21088294).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.29
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• EAST syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• enlarged vestibular aqueduct syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003523914: Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 19420365, 20807765, 21088294).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002241.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 2.7053 (below the threshold of 3.09). GenCC associations: The gene is linked to EAST syndrome, Pendred syndrome, enlarged vestibular aqueduct syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 1-160042304-C-G is Pathogenic according to our data. Variant chr1-160042304-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7468.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002241.5. 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
	KCNJ10	NM_002241.5	MANE Select	c.229G>C	p.Gly77Arg	missense	Exon 2 of 2	NP_002232.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	ENST00000644903.1	MANE Select	c.229G>C	p.Gly77Arg	missense	Exon 2 of 2	ENSP00000495557.1	P78508
	KCNJ10	ENST00000638728.1	TSL:5	c.229G>C	p.Gly77Arg	missense	Exon 3 of 3	ENSP00000492619.1	P78508
	KCNJ10	ENST00000638868.1	TSL:5	c.229G>C	p.Gly77Arg	missense	Exon 3 of 3	ENSP00000491250.1	P78508

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	EAST syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.95		Gain of methylation at G77 (P = 0.0159)
MVP		0.99
MPC		1.5
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		0.024	Neutral
Varity_R		0.85
gMVP		0.99
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs137853072; hg19: chr1-160012094;