21-37625299-C-T

Position:

• chr21-37625299-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_002240.5(KCNJ6):​c.1132G>A​(p.Glu378Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KCNJ6 NM_002240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.11

Genes affected

KCNJ6 (HGNC:6267): (potassium inwardly rectifying channel subfamily J member 6) This gene encodes a member of the G protein-coupled inwardly-rectifying potassium channel family of inward rectifier potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it. These proteins modulate many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells, through G-protein coupled receptor stimulation. Mutations in this gene are associated with Keppen-Lubinsky Syndrome, a rare condition characterized by severe developmental delay, facial dysmorphism, and intellectual disability. [provided by RefSeq, Apr 2015]

ENSG00000286717 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ6. . Gene score misZ 3.7134 (greater than the threshold 3.09). Trascript score misZ 4.9887 (greater than threshold 3.09). GenCC has associacion of gene with Keppen-Lubinsky syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23923686).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.1132G>A	p.Glu378Lys	missense_variant	4/4	ENST00000609713.2	NP_002231.1
KCNJ6-AS1	NR_183540.1	n.408-73256C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.1132G>A	p.Glu378Lys	missense_variant	4/4	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.1132G>A	p.Glu378Lys	missense_variant	5/5			ENSP00000493772.1
ENSG00000286717	ENST00000667151.1	n.161-21248C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2021

The c.1132G>A (p.E378K) alteration is located in exon 4 (coding exon 3) of the KCNJ6 gene. This alteration results from a G to A substitution at nucleotide position 1132, causing the glutamic acid (E) at amino acid position 378 to be replaced by a lysine (K). Based on data from the Genome Aggregation Database (gnomAD), the KCNJ6 c.1132G>A alteration was not observed, with coverage at this position. This amino acid position is well conserved in available vertebrate species. The p.E378K alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.0056
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.11	N;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.82	T;.
Polyphen		0.13	B;B
Vest4		0.32
MutPred		0.54		Gain of MoRF binding (P = 0.0049);Gain of MoRF binding (P = 0.0049);
MVP		0.10
MPC		1.3
ClinPred		0.37	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs777214818; hg19: chr21-38997601; COSMIC: COSV55713458;