NM_002241.5:c.1054C>A

Variant names:

• chr1-160041479-G-T
• rs888967595
• NM_002241.5:c.1054C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_002241.5(KCNJ10):​c.1054C>A​(p.Pro352Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14080685).

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.1054C>A	p.Pro352Thr	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.1054C>A	p.Pro352Thr	missense	Exon 2 of 2	ENSP00000495557.1
	KCNJ10	ENST00000638728.1	TSL:5	c.1054C>A	p.Pro352Thr	missense	Exon 3 of 3	ENSP00000492619.1
	KCNJ10	ENST00000638868.1	TSL:5	c.1054C>A	p.Pro352Thr	missense	Exon 3 of 3	ENSP00000491250.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251364 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EAST syndrome Uncertain:1

Jan 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 578643). This variant has not been reported in the literature in individuals affected with KCNJ10-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 352 of the KCNJ10 protein (p.Pro352Thr).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.22
Sift	Benign	0.36	T
Sift4G	Benign	0.71	T
Polyphen		0.0050	B
Vest4		0.13
MVP		0.18
MPC		0.59
ClinPred		0.052	T
GERP RS		4.2
PromoterAI		0.0067	Neutral
Varity_R		0.073
gMVP		0.32
Mutation Taster		=88/12	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: rs888967595; hg19: chr1-160011269;