rs199565947

Variant names:

• chr12-49557459-C-T
• rs199565947
• NM_012284.3:c.2758C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012284.3(KCNH3):​c.2758C>T​(p.Arg920Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,610,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (2 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0830
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06886205).
• BS2: High AC in GnomAd4 at 10 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.2758C>T	p.Arg920Trp	missense	Exon 15 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.2578C>T	p.Arg860Trp	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.2758C>T	p.Arg920Trp	missense	Exon 15 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.2524C>T	p.Arg842Trp	missense	Exon 14 of 14	ENSP00000635217.1
	MCRS1	ENST00000551598.5	TSL:5	c.430-709G>A		intron	N/A	ENSP00000448947.1	H0YIA0

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000114 AC: 28 AN: 245050 AF XY: 0.0000826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000635

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.0000747 AC: 109 AN: 1458236 Hom.: 2 Cov.: 33 AF XY: 0.0000662 AC XY: 48 AN XY: 725328

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.000449 AC: 20 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51862

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1110794

Other (OTH) AF: 0.0000830 AC: 5 AN: 60254

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74498

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.069	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.34	N
PhyloP100		-0.083
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.029	D
Polyphen		0.79	P
Vest4		0.29
MVP		0.67
MPC		0.59
ClinPred		0.043	T
GERP RS		0.78
Varity_R		0.053
gMVP		0.23
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199565947; hg19: chr12-49951242; COSMIC: COSV57790893; COSMIC: COSV57790893;