rs145588542

Variant names:

• chr1-160041441-T-C
• rs145588542
• NM_002241.5:c.1092A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002241.5(KCNJ10):​c.1092A>G​(p.Gln364Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,614,038 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (36 hom.)
• Consequence: KCNJ10 NM_002241.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.628
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-160041441-T-C is Benign according to our data. Variant chr1-160041441-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137981.
• BP7: Synonymous conserved (PhyloP=-0.628 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00327 (498/152334) while in subpopulation NFE AF = 0.00603 (410/68030). AF 95% confidence interval is 0.00555. There are 1 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR,AD gene

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.1092A>G	p.Gln364Gln	synonymous	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.1092A>G	p.Gln364Gln	synonymous	Exon 2 of 2	ENSP00000495557.1	P78508
	KCNJ10	ENST00000638728.1	TSL:5	c.1092A>G	p.Gln364Gln	synonymous	Exon 3 of 3	ENSP00000492619.1	P78508
	KCNJ10	ENST00000638868.1	TSL:5	c.1092A>G	p.Gln364Gln	synonymous	Exon 3 of 3	ENSP00000491250.1	P78508

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 498 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00388 AC: 974 AN: 251166 AF XY: 0.00393

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00680

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00595 AC: 8695 AN: 1461704 Hom.: 36 Cov.: 31 AF XY: 0.00580 AC XY: 4216 AN XY: 727162

African (AFR) AF: 0.000717 AC: 24 AN: 33474

American (AMR) AF: 0.00136 AC: 61 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

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

South Asian (SAS) AF: 0.00306 AC: 264 AN: 86236

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53412

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5692

European-Non Finnish (NFE) AF: 0.00721 AC: 8020 AN: 1111960

Other (OTH) AF: 0.00407 AC: 246 AN: 60382

GnomAD4 genome AF: 0.00327 AC: 498 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74500

African (AFR) AF: 0.000962 AC: 40 AN: 41576

American (AMR) AF: 0.00209 AC: 32 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00469 Hom.: 0

Bravo AF: 0.00316

EpiCase AF: 0.00643

EpiControl AF: 0.00623

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	EAST syndrome (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		-0.63
Mutation Taster		=100/0	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: rs145588542; hg19: chr1-160011231; COSMIC: COSV104677768;