12-49542745-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012284.3(KCNH3):​c.485G>C​(p.Gly162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,000 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: 7.0e-7 (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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2705816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.485G>C	p.Gly162Ala	missense_variant	Exon 4 of 15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.305G>C	p.Gly102Ala	missense_variant	Exon 4 of 15		NP_001300959.1
KCNH3	XM_011538085.3	c.485G>C	p.Gly162Ala	missense_variant	Exon 4 of 15		XP_011536387.1
KCNH3	XM_047428613.1	c.485G>C	p.Gly162Ala	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>C	p.Gly162Ala	missense_variant	Exon 4 of 15	1	NM_012284.3	ENSP00000257981.5
KCNH3	ENST00000550434.1	n.214G>C		non_coding_transcript_exon_variant	Exon 3 of 5	3
KCNH3	ENST00000649994.1	n.*95G>C		non_coding_transcript_exon_variant	Exon 5 of 16			ENSP00000497890.1
KCNH3	ENST00000649994.1	n.*95G>C		3_prime_UTR_variant	Exon 5 of 16			ENSP00000497890.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437000 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.27	T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.46
Sift	Benign	0.21	T
Sift4G	Benign	0.24	T
Polyphen		0.63	P
Vest4		0.23
MutPred		0.26		Gain of helix (P = 0.0199);
MVP		0.93
MPC		1.5
ClinPred		0.65	D
GERP RS		3.5
Varity_R		0.18
gMVP		0.65

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;