NM_012284.3:c.554C>G

Variant names:

• chr12-49542814-C-G
• NM_012284.3:c.554C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012284.3(KCNH3):​c.554C>G​(p.Pro185Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

Genes affected

KCNH3 (HGNC:6252): (potassium voltage-gated channel subfamily H member 3) The protein encoded by this gene is a voltage-gated potassium channel alpha subunit predominantly expressed in the forebrain. Studies in mice have found that cognitive function increases when this gene is knocked out. In humans, the encoded protein has been shown to be capable of binding glycoprotein 120 of the human immunodeficiency virus type 1 (HIV-1) envelope. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

KCNH3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15118483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH3	NM_012284.3	MANE Select	c.554C>G	p.Pro185Arg	missense	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.374C>G	p.Pro125Arg	missense	Exon 4 of 15	NP_001300959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH3	ENST00000257981.7	TSL:1 MANE Select	c.554C>G	p.Pro185Arg	missense	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.320C>G	p.Pro107Arg	missense	Exon 3 of 14	ENSP00000635217.1
	KCNH3	ENST00000550434.1	TSL:3	n.283C>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.073	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	-0.97	N
PhyloP100		2.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.040	N
REVEL	Uncertain	0.38
Sift	Benign	0.42	T
Sift4G	Benign	0.40	T
Polyphen		0.82	P
Vest4		0.21
MutPred		0.26		Gain of MoRF binding (P = 0.0212)
MVP		0.83
MPC		1.2
ClinPred		0.43	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.49
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

hg19: chr12-49936597;