17-70132496-C-G

Position:

• chr17-70132496-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_170741.4(KCNJ16):​c.409C>G​(p.Arg137Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ16 NM_170741.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.86

Genes affected

KCNJ16 (HGNC:6262): (potassium inwardly rectifying channel subfamily J member 16) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which tends to allow potassium to flow into rather than out of a cell, can form heterodimers with two other inward-rectifier type potassium channels. It may function in fluid and pH balance regulation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

KCNJ16 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-70132496-C-G is Pathogenic according to our data. Variant chr17-70132496-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2571001.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ16	NM_170741.4	c.409C>G	p.Arg137Gly	missense_variant	4/4	ENST00000392671.6	NP_733937.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ16	ENST00000392671.6	c.409C>G	p.Arg137Gly	missense_variant	4/4	2	NM_170741.4	ENSP00000376439.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

KCNJ16: PP4:Strong, PM2, PM5, PM3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;.;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;H;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.7	D;D;.;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;.
Vest4		0.93
MutPred		0.86		Gain of catalytic residue at V139 (P = 0.1137);Gain of catalytic residue at V139 (P = 0.1137);Gain of catalytic residue at V139 (P = 0.1137);Gain of catalytic residue at V139 (P = 0.1137);.;Gain of catalytic residue at V139 (P = 0.1137);.;
MVP		0.93
MPC		0.40
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.94

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: chr17-68128637;