21-37625410-T-A

Position:

• chr21-37625410-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002240.5(KCNJ6):​c.1021A>T​(p.Thr341Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ6 NM_002240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.32596844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.1021A>T	p.Thr341Ser	missense_variant	4/4	ENST00000609713.2	NP_002231.1
KCNJ6-AS1	NR_183540.1	n.408-73145T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.1021A>T	p.Thr341Ser	missense_variant	4/4	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.1021A>T	p.Thr341Ser	missense_variant	5/5			ENSP00000493772.1
ENSG00000286717	ENST00000667151.1	n.161-21137T>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 25, 2023

This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ6 protein function. This variant has not been reported in the literature in individuals affected with KCNJ6-related conditions. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 341 of the KCNJ6 protein (p.Thr341Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Uncertain	0.55	D;D
Eigen	Benign	-0.20
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.59	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.58	T;.
Polyphen		0.0020	B;B
Vest4		0.66
MutPred		0.34		Loss of phosphorylation at T337 (P = 0.1148);Loss of phosphorylation at T337 (P = 0.1148);
MVP		0.13
MPC		1.0
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.19
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38997712;