chr1-160041410-G-C

Variant names:

• chr1-160041410-G-C
• rs751338154
• NM_002241.5:c.1123C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002241.5(KCNJ10):​c.1123C>G​(p.Arg375Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,576 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 4 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: Orphanet, Ambry Genetics, PanelApp Australia, G2P, 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 3 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	NM_002241.5	MANE Select	c.1123C>G	p.Arg375Gly	missense	Exon 2 of 2	NP_002232.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	ENST00000644903.1	MANE Select	c.1123C>G	p.Arg375Gly	missense	Exon 2 of 2	ENSP00000495557.1
	KCNJ10	ENST00000638728.1	TSL:5	c.1123C>G	p.Arg375Gly	missense	Exon 3 of 3	ENSP00000492619.1
	KCNJ10	ENST00000638868.1	TSL:5	c.1123C>G	p.Arg375Gly	missense	Exon 3 of 3	ENSP00000491250.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460576 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726568

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5112

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000178 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.0088	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.37
MutPred		0.30		Loss of MoRF binding (P = 3e-04)
MVP		0.82
MPC		0.98
ClinPred		0.85	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.75
Mutation Taster		=53/47	polymorphism

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: rs751338154; hg19: chr1-160011200;