6-39317796-C-T

Position:

• chr6-39317796-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135106.2(KCNK16):​c.485G>A​(p.Arg162Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNK16 NM_001135106.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

KCNK16 (HGNC:14464): (potassium two pore domain channel subfamily K member 16) The protein encoded by this gene belongs to the family of potassium channel proteins containing two pore-forming P domains. This channel is an open rectifier which primarily passes outward current under physiological K+ concentrations. This gene is expressed predominantly in the pancreas and is activated at alkaline pH. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Sep 2008]

LOC105375047 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12228039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK16	NM_001135106.2	c.485G>A	p.Arg162Lys	missense_variant	3/5	ENST00000437525.3	NP_001128578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK16	ENST00000437525.3	c.485G>A	p.Arg162Lys	missense_variant	3/5	1	NM_001135106.2	ENSP00000415375.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447906 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718968

Gnomad4 AFR exome AF: 0.0000901

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.485G>A (p.R162K) alteration is located in exon 3 (coding exon 3) of the KCNK16 gene. This alteration results from a G to A substitution at nucleotide position 485, causing the arginine (R) at amino acid position 162 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.00096	T;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.55	T;T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;L;.;L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.95	T;T;T;T;T
Sift4G	Benign	0.95	T;T;T;T;T
Polyphen		0.0080	B;B;.;B;.
Vest4		0.20
MutPred		0.39		Gain of ubiquitination at R162 (P = 0.0247);Gain of ubiquitination at R162 (P = 0.0247);.;Gain of ubiquitination at R162 (P = 0.0247);Gain of ubiquitination at R162 (P = 0.0247);
MVP		0.35
MPC		0.20
ClinPred		0.27	T
GERP RS		3.5
Varity_R		0.080
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1762374934; hg19: chr6-39285572;