12-49542735-C-T

Variant names:

• chr12-49542735-C-T
• rs1273768005
• NM_012284.3:c.475C>T

Variant summary

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

The NM_012284.3(KCNH3):​c.475C>T​(p.Arg159*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,433,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNH3 NM_012284.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.475C>T	p.Arg159*	stop_gained	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.295C>T	p.Arg99*	stop_gained	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.475C>T	p.Arg159*	stop_gained	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.241C>T	p.Arg81*	stop_gained	Exon 3 of 14	ENSP00000635217.1
	KCNH3	ENST00000550434.1	TSL:3	n.204C>T		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433340 Hom.: 0 Cov.: 31 AF XY: 0.00000422 AC XY: 3 AN XY: 710154

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 40010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 38498

South Asian (SAS) AF: 0.00 AC: 0 AN: 81956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1098908

Other (OTH) AF: 0.00 AC: 0 AN: 59264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00955443), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		1.4
Vest4		0.13
GERP RS		1.6
Mutation Taster		=21/179	disease causing (fs/PTC)

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

dbSNP: rs1273768005; hg19: chr12-49936518;