12-49542745-G-A

Variant names:

• chr12-49542745-G-A
• rs544415516
• NM_012284.3:c.485G>A

Variant summary

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

The NM_012284.3(KCNH3):​c.485G>A​(p.Gly162Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,436,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95

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]

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=0.20873877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.485G>A	p.Gly162Asp	missense_variant	Exon 4 of 15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.305G>A	p.Gly102Asp	missense_variant	Exon 4 of 15		NP_001300959.1
KCNH3	XM_011538085.3	c.485G>A	p.Gly162Asp	missense_variant	Exon 4 of 15		XP_011536387.1
KCNH3	XM_047428613.1	c.485G>A	p.Gly162Asp	missense_variant	Exon 4 of 10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7	c.485G>A	p.Gly162Asp	missense_variant	Exon 4 of 15	1	NM_012284.3	ENSP00000257981.5
KCNH3	ENST00000550434.1	n.214G>A		non_coding_transcript_exon_variant	Exon 3 of 5	3
KCNH3	ENST00000649994.1	n.*95G>A		non_coding_transcript_exon_variant	Exon 5 of 16			ENSP00000497890.1
KCNH3	ENST00000649994.1	n.*95G>A		3_prime_UTR_variant	Exon 5 of 16			ENSP00000497890.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000489 AC: 1 AN: 204388 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 110288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000648

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436998 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.0	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.58
Sift	Benign	0.12	T
Sift4G	Benign	0.26	T
Polyphen		0.27	B
Vest4		0.50
MutPred		0.27		Gain of loop (P = 0.0435);
MVP		0.94
MPC		1.4
ClinPred		0.31	T
GERP RS		3.5
Varity_R		0.23
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs544415516; hg19: chr12-49936528;