6-39317909-G-C

Position:

• chr6-39317909-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001135106.2(KCNK16):​c.372C>G​(p.Phe124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNK16 NM_001135106.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK16	NM_001135106.2	c.372C>G	p.Phe124Leu	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.372C>G	p.Phe124Leu	missense_variant	3/5	1	NM_001135106.2	ENSP00000415375.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 21, 2023

The c.372C>G (p.F124L) alteration is located in exon 3 (coding exon 3) of the KCNK16 gene. This alteration results from a C to G substitution at nucleotide position 372, causing the phenylalanine (F) at amino acid position 124 to be replaced by a leucine (L). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.059	T;D;D;D;T
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		1.0	D;D;.;P;.
Vest4		0.92
MutPred		0.60		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.35
MPC		0.82
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.64
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-39285685;