rs1273768005

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-49542735-C-G
• chr12-49542735-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_012284.3(KCNH3):​c.475C>G​(p.Arg159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04903835).
• BP6: Variant 12-49542735-C-G is Benign according to our data. Variant chr12-49542735-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3532360.Status of the report is criteria_provided_single_submitter, 1 stars.

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>G	p.Arg159Gly	missense	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.295C>G	p.Arg99Gly	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.475C>G	p.Arg159Gly	missense	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.241C>G	p.Arg81Gly	missense	Exon 3 of 14	ENSP00000635217.1
	KCNH3	ENST00000550434.1	TSL:3	n.204C>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000100 AC: 2 AN: 199022 AF XY: 0.00000933

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433340 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710154

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: 0.00000182 AC: 2 AN: 1098908

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	0.041
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.049	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-0.49	N
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.25
Sift	Benign	0.50	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.35		Loss of methylation at R159 (P = 0.0101)
MVP		0.31
MPC		1.4
ClinPred		0.025	T
GERP RS		1.6
Varity_R		0.066
gMVP		0.71
Mutation Taster		=96/4	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

dbSNP: rs1273768005; hg19: chr12-49936518;