rs148404630

Variant names:

• chr12-49557408-C-G
• rs148404630
• NM_012284.3:c.2707C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49557408-C-G
• chr12-49557408-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012284.3(KCNH3):​c.2707C>G​(p.Arg903Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,600,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R903C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• 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]

MCRS1 (HGNC:6960): (microspherule protein 1) Enables RNA binding activity and telomerase inhibitor activity. Involved in histone H4 acetylation; negative regulation of DNA metabolic process; and positive regulation of protein localization to nucleolus. Located in cytoplasm; nucleolus; and nucleoplasm. Part of Ino80 complex; MLL1 complex; and histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.2707C>G	p.Arg903Gly	missense	Exon 15 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.2527C>G	p.Arg843Gly	missense	Exon 15 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.2707C>G	p.Arg903Gly	missense	Exon 15 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.2473C>G	p.Arg825Gly	missense	Exon 14 of 14	ENSP00000635217.1
	MCRS1	ENST00000551598.5	TSL:5	c.430-658G>C		intron	N/A	ENSP00000448947.1	H0YIA0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000829 AC: 2 AN: 241316 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000925

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448572 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718624

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 84880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1103586

Other (OTH) AF: 0.0000167 AC: 1 AN: 59776

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.55	N
PhyloP100		2.2
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.74
Sift	Benign	0.080	T
Sift4G	Benign	0.38	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.47		Loss of MoRF binding (P = 0.0089)
MVP		0.97
MPC		0.36
ClinPred		0.53	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.60
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

dbSNP: rs148404630; hg19: chr12-49951191;