1-160042228-G-C

Variant names:

• chr1-160042228-G-C
• rs372156619
• NM_002241.5:c.305C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_002241.5(KCNJ10):​c.305C>G​(p.Pro102Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,198 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.76
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• 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, enlarged vestibular aqueduct syndrome, Pendred syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

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.305C>G	p.Pro102Arg	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.305C>G	p.Pro102Arg	missense	Exon 2 of 2	ENSP00000495557.1	P78508
	KCNJ10	ENST00000638728.1	TSL:5	c.305C>G	p.Pro102Arg	missense	Exon 3 of 3	ENSP00000492619.1	P78508
	KCNJ10	ENST00000638868.1	TSL:5	c.305C>G	p.Pro102Arg	missense	Exon 3 of 3	ENSP00000491250.1	P78508

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110768

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	EAST syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.027	D
Sift4G	Benign	0.18	T
Polyphen		0.96	D
Vest4		0.38
MutPred		0.37		Loss of catalytic residue at P101 (P = 0.016)
MVP		0.70
MPC		1.3
ClinPred		0.97	D
GERP RS		5.3
PromoterAI		-0.0032	Neutral
Varity_R		0.16
gMVP		0.96
Mutation Taster		=41/59	disease causing

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: rs372156619; hg19: chr1-160012018;